CN105853351A - Linezolid oral suspension and preparation method theroef - Google Patents
Linezolid oral suspension and preparation method theroef Download PDFInfo
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- CN105853351A CN105853351A CN201610202729.6A CN201610202729A CN105853351A CN 105853351 A CN105853351 A CN 105853351A CN 201610202729 A CN201610202729 A CN 201610202729A CN 105853351 A CN105853351 A CN 105853351A
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- 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
- A61K9/10—Dispersions; Emulsions
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
Abstract
The invention belongs to the field of pharmaceutic preparation, and specifically a linezolid oral suspension and a preparation method thereof. The linezolid oral suspension comprises the following components by weight: 0.5-2.0 parts of linezolid, 0.5-5.0 parts of sodium carboxymethyl cellulose, 0.05-0.5 part of polysorbate 80, 0.15-0.20 part of sodium citrate, 0.08-0.10 part of citric acid, 0.22-0.28 part of a preservative, 22-28 parts of sweetener, 1.2-1.8 parts of a correctant and an aqueous medium. The present invention fills the market blank of only containing tablet or injection, and provides a novel dosage form choice. The linezolid oral suspension product has good quality, can be accurately divided into the dosage based on body weight, and is easy to swallow. The preparation process is simple, feasible and reproducible, and can consistently produce linezolid oral suspension with quality meeting the requirements.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of Linezolid oral administration mixed suspension and preparation method thereof.
Background technology
Linezolid is first antibiotic of brand new class obtaining listing license in Oxazolidinone derivative, its by
Upjohn company develops, and 2000, FDA ratified its list marketing, was used for treating Grain-positive (G+) coccigenic infection, bag
Include by cause doubtful of MRSA or make a definite diagnosis nosocomial pneumonia (HAP), community acquired pneumonia (CAP), complexity skin or
Skin soft-tissue infection (SSTI) and vancomycin-resistant enterococcus (VRE) infection etc..
Linezolid is bacterioprotein synthetic inhibitor, acts on bacterium 50S ribosomal subunit, and closest to making
Use position.Different from other medicines, Linezolid does not affect peptidyl transferase activity, simply acts on the initial rank of translation system
Section, suppression mRNA is connected with ribosomes, stops the formation of 70S initiation complex, thus inhibits the synthesis of bacterioprotein.
Between the Pharmacological Mechanism of Linezolid, it is in clinical practice, and patient can be made to obtain bigger interests:
1) it is not susceptible to crossing drug resistant: the site of action of Linezolid and mode are unique, therefore have internal or are obtaining
Obtain in the positive bacteria of property drug-resistance characteristics, be all difficult to and antimicrobial generation crossing drug resistant of other suppression albumen synthesis.
2) bioavilability is high: Linezolid is that unique oral administration biaavailability is almost identical with intravenous administration novel
Antibiotic, absorbs rapidly.Its oral administration biaavailability nearly reaches 100%, clinical when intravenously administrable is changed to oral administration, nothing
Dosage adjustment must be carried out.
3) crowd it is suitable for wide: neonate to gerontal patient all can use.Gerontal patient, in various degree renal insufficiency patient
Dosage adjustment need not be carried out with mild to moderate dyshepatia patient.
4) has a broad antifungal spectrum: most of bacterial strains are had antibacterial activity, causes a disease including aerobic He facultative Gram-positive
Bacterium, VREF (only refers to the bacterial strain of drug resistance of vancomycin), and staphylococcus aureus (includes the bacterial strain of methicillin resistance), nothing
Streptococcus lactis, streptococcus pneumonia (including the bacterial strain to MDR [MDRSP]), micrococcus scarlatinae.
5) determined curative effect: clinical efficacy is superior to or is equal to conventional antimicrobial medicine.And only to specified microorganisms sensitive strain
Caused infection is effective, can prevent the abuse of antibiotic, is that the Conventional antibiotic such as vancomycin, methicillin is produced resistance to by human body
Ideal chose after the property of medicine, is the first selection of nosocomial pneumonia.
The preparation of at present both at home and abroad Linezolid market sale, drug-delivery preparation is oral solid tablet and quiet the most clinically
Two kinds of formulations of arteries and veins infusion solutions.Both formulations all have shortcoming, such as oral solid tablet, although carry, clinical application, patient take medicine
Compliance relatively infusion solutions is convenient, but due to the bigger 0.6g of oral tablet specification, adds auxiliary material, and slice, thin piece is close to about 0.9g, slice, thin piece
Excessive, for the patient of children, old man or other dysphagias, difficulty of taking medicine;Separately to 7 days or above neonate or its
For the children of his age bracket, clinical application must press the 10mg/kg dosed administration Linezolid of for every eight hours or 12 hours, therefore,
The neonate of different weight or children are according to body weight, and its dosage taking Linezolid is different, but oral tablet is excessive, and
Harder, divided dose is more difficult, and inaccurate.Additionally, vein infusion solutions is for general patient, takes medicine more inconvenient, need to go
Hospital or clinic carry out intravenous drip, and another safety risks relatively oral formulations is high.Patent of invention CN102973500 provides one
Kind of Linezolid liquid preparation and preparation method thereof, component be Linezolid, citric acid, citric acid receive, sodium chloride, injection
Water, said preparation is parenteral solution, and understanding it from prescription does not has oral liquid to commonly use auxiliary material, and such as flavouring, sweetener etc. are complete
It is all injection and commonly uses auxiliary material;Its method is also the preparation technology of parenteral solution, parenteral liquid preparation and preparation method thereof.
Patent of invention CN201310607446.6 provides the preparation method of a kind of high stable Linezolid Injection, group
Being divided into Linezolid, glucose, sodium dihydrogen phosphate or phosphoric acid, water for injection, said preparation is parenteral solution, and its method is also parenteral solution
Preparation technology, parenteral liquid preparation and preparation method thereof.
Patent of invention CN201210525618.0, CN201410401123.6, CN201510567368.0,
CN201210581947.7, CN201110207573.8 are each provided with a kind of Linezolid oral tablet and preparation method thereof,
Contained material is tablet routine material, such as mannitol, lactose, microcrystalline cellulose, PVPP, polyethylene glycol, Bo Luosha
Nurses etc., its preparation method is also that the common process using tablet is prepared.This type of oral solid formulation yet suffers from being difficult to point
After dosage, divided dose, dosage is inaccurate, slice, thin piece specification is difficult to greatly the shortcoming swallowed.
Lyophilized buccal tablet providing a kind of children's in patent of invention CN201210732013.3 and preparation method thereof, should
The materials such as patent prescription is received containing Linezolid, mannitol, gelatin, citric acid, Sucralose, sodium acid carbonate, this patented composition
There is some superiority, it is not necessary to water, it is not necessary to chew, 4s clock energy fater disintegration.But still there is children's and need to give Li Nai according to body weight
The problem that azoles amine is difficult to divided dose;Even if another oral disnitegration tablet of the present invention is fast again, also need redisperse after solid state is disintegrated
Process and play drug effect, compared with liquid preparation, its disintegration play curative effect the slowest.Additionally, the present invention uses freeze-drying mode
Prepare tablet, need special freeze drying equipment, process cycle length and complexity, manufacturing cost high, Linezolid main ingredient specification own
Relatively big, such as listing oral tablet main ingredient specification is 0.6g, and cost of material is high, adds the manufacturing cost of great number, necessarily gives and suffer from
Person increases financial burden.
Carry between high-capacity injection, clinical application is inconvenient, patient's poor compliance, and oral solid formulation is difficult to a point agent
Amount or the inaccurate feature of divided dose, therefore, be necessary to develop one at present and take medicine conveniently, be prone to divided dose and dosage accurately
Preparation.It is blank, for Grain-positive (G+) coccigenic infected patient that the Linezolid suspendible oral liquid of the present invention can fill up this
A kind of carrying convenience, the oral liquid of divided dose of taking medicine conveniently, be prone to are provided.
Summary of the invention
In view of this, it is an object of the invention to provide profit that a kind of Linezolid composition and preparation method prepare how azoles
Amine oral administration mixed suspension, has filled up and has only had tablet, the blank of parenteral solution in market, it is provided that new dosage form selection;This Linezolid
Oral administration mixed suspension good quality of product;And accurate divided dose can be carried out according to body weight, it is easy to swallow, for children, old man and other
Dysphagia patients is provided convenience;The preparation method of the present invention shows through pilot scale and trial production amplification, and this technique is simple, can
OK, and there is reappearance, can the uniform Linezolid oral administration mixed suspension producing satisfactory quality.
For achieving the above object, the technical scheme is that
A kind of Linezolid oral administration mixed suspension, includes following components in parts by weight: Linezolid 0.5~2.0 parts, carboxylic
Sodium carboxymethylcellulose pyce 0.5~5.0 parts, pH combination conditioning agent 0.23~0.30 part and aqueous medium.
Preferred as one, described Linezolid is Linezolid micro mist.
Suspendible oral liquid is to determine according to main ingredient dissolution characteristics in water, and Linezolid is polymorph medicine, uses at present
Being usually II type crystalline substance familial combined hyperlipidemia in preparation brilliant, wherein II type crystalline substance is the most stable, and IV type crystalline substance is easily converted into II type in the case of damp and hot
Brilliant.The dissolubility of two kinds of crystal formations is essentially identical, is slightly soluble medicine, and in water, solubility is less, (is shown in Table for about 3.0mg/ml
1, table 2), therefore, the Linezolid of 0.6g main ingredient specification is prepared as solution-type parenteral solution or oral liquid, at least needs 200ml water,
Placing easy crystallization for 2~8 DEG C under this concentration conditions, the concentration of dissolving is the biggest, the most saturated, crystallization the most serious (being shown in Table 3).In order to protect
Card dissolve after main ingredient not crystallization body, at least want 300ml and more than, as import list Linezolid Injection be 300ml:0.6g
Main ingredient or 150ml:0.3g main ingredient.Visible, if making solution-type oral liquid at least need 300ml or 150ml water, this is for suffering from
Person is difficult to accept, especially children, and liquor capacity is too big, poor compliance.Therefore, in order to improve patient's compliance, often it is prepared as
The oral liquid of rule small size specification (such as 5ml, 10ml etc.), in combination with Linezolid solubility, this product is only suitable for preparing suspendible
Type oral liquid, rather than solution-type oral liquid.
Table 1 crystal formation II and the apparent solubility of crystal formation IV
Solvent | Crystal formation II solubility (mg/ml) | Crystal formation IV solubility (mg/ml) | Dissolubility |
Water | 2.8 | 3.0 | Slightly soluble |
Table 2 bulk drug dissolves situation in the different pH value aqueous solution
Medium | Water | pH1.1 | pH4.0 | pH5.0 |
Solubility | 1mg/100ml | 0.1mg/100ml | 0.1mg/100ml | 0.2mg/100ml |
Dissolubility under table 3 distinct temperature investigates result
Note: " " expression has no that crystal separates out, "+" represent that slightly crystal separates out, multiple "+" represent that crystal separates out serious journey
Degree.
In described Linezolid oral administration mixed suspension, Linezolid particulate is normal distribution.
In described Linezolid oral administration mixed suspension, sodium carboxymethylcellulose is suspending agent, and suspending agent is the most crucial, its effect
Predominantly suspending, slowly settles after making particulate matter shaking, is suspended in solution, it is to avoid settles too fast between particulate, is sunken to the end
Portion, sized particles generation tessellation, there is particulate caking phenomenon, affects drug quality in long-term placement.Conventional suspending agent has
Gelatin, Arabic gum, xanthans, polyvinylpyrrolidone, sodium carboxymethylcellulose, HPMC etc..Variety classes
Suspending agent there is different physicochemical properties, such as viscosity, surface charge and active component compatibility etc..The present invention preferred carboxylic first
Base sodium cellulosate, after dissolving clarification in water because of sodium carboxymethylcellulose, negative electrical charge on solution band, when particulate matter main ingredient adds
After solution, can make negative electrical charge homogeneous on microparticle surfaces band, this is conducive to the physical stability of particulate, arranges each other between particulate
Scold, it is to avoid particulate caking, beneficially product are stable.
Sodium carboxymethylcellulose is as suspending agent, and the concentration of suspending agent also affects the suspending effect of particulate, and concentration is the biggest, helps
The viscosity of suspension is the strongest, and suspending effect is the best, but concentration is excessive, and viscosity is too strong, can cause filtration difficulty, viscous chamber wall, residual
Measure too much problem;Suspending agent concentration is too low, and viscosity is too small, suspended particles sedimentation resistance can be caused again little, settle too fast, unfavorable
It is administered completely when clinical application.Additionally, particulate self property and size, suspending agent kind and consumption all can be to products as previously mentioned
The suspendible flocculating effect of product produces impact, and the two has certain relativity, as particulate is big, and weight, inevitable requirement suspending agent concentration
Relatively a little bigger, enough viscosity could stop the rapid subsidence of particulate, anyway, particulate is little, gently, it is only necessary to suitable less concentration
Suspending agent i.e. can reach effective flocculation and suspending effect.Particle size of the present invention and the selection of suspending agent, from prior art
It is difficult to well be pointed out and imply, it is necessary to through substantial amounts of experiment sieving gained.Big at phase Linezolid particulate of the present invention
In little and sodium carboxymethylcellulose concentration range, prepare product suspension solution sedimentation volume ratio and be all higher than 0.95 (2015 editions pharmacopeia
Requirement is 0.9~1.0), sedimentation volume ratio is the biggest, shows that flocculating effect is the best, the loosest between particulate, cotton-shaped in cotton, has
It is beneficial to the stablizing of particulate, does not lumps, place after June also without caking phenomenon for long-term 40 DEG C.And comparative example 1, comparative example 2
Middle product flocculating effect is poor, and sedimentation volume ratio only has 0.83,0.75, long-term 40 DEG C place June after have caking phenomenon.
Further, in described Linezolid oral administration mixed suspension, Linezolid particle size D90 is 10~150 μm.
As it was previously stated, Linezolid solubility in water is less, suitably preparing suspendible oral liquid, therefore Linezolid is at mouth
Take in liquid and exist with particulate hybrid state.In mixed suspension preparation, particle size and uniformity can affect the physically stable of mixed suspension preparation
Property, such as agglomeration problems in storage process.Particulate is excessive, overweight, and sinking speed is too fast, and product places easily caking for a long time;Additionally
If drug microparticles is quickly sunken to bottom, it is not easy to during clinical application take medicine completely.Particulate is too small, though being beneficial to suspend in the solution,
But too small can accelerate its dissolve, easily cause recrystallization after dissolving, crystal is grown up, thus affects product quality;Another particulate is meticulous, than
Surface area increases, and surface free energy increases, and particulate has and stronger gathers unstability, is easier to the most agglomerated together knot
Block phenomenon.In the present invention, Linezolid diameter of particle controls at D90 is 10~150 μm, and particulate is normal distribution, can be prevented effectively from
The excessive too small agglomeration problems caused of particulate.
Preferred as one, in described Linezolid oral administration mixed suspension, Linezolid particle size D90 is 50~100 μm.
Further, the pH value of described Linezolid oral administration mixed suspension is 4.2~5.2.
Preferred as one, the pH value of described Linezolid oral administration mixed suspension is 4.9.
Linezolid stability in water, with pH has relatively Important Relations, research to show that Linezolid is in the range of 4.2-5.2
Stability is relatively preferably (being shown in Table 4).PH adjusting agent of the present invention is chosen as sodium citrate and citric acid, and sodium citrate and described Chinese holly
The weight part ratio of rafter acid is: 0.15~0.20:0.08~0.10, and the oral liquid pH value obtained is the most fixing, and pH value exists
About 4.9, for the optimal pH of Linezolid stability.
Table 4 Linezolid steadiness in different pH value
Further, the described pH combination concrete composition of conditioning agent is sodium citrate and citric acid, and described sodium citrate is with described
The weight part ratio of citric acid is: 0.15~0.20:0.08~0.10.
According to Linezolid chemically stable implementations, simultaneously in order to simplify pH regulation technique, the present invention combines conditioning agent and is
Sodium citrate and citric acid, sodium citrate of the present invention also has another key factor with the selection of citric acid, and the combination of this pH value is adjusted
Joint agent will not produce opalescence phenomenon to this product suspendible oral liquid, and oral administration solution can breast when selecting phosphoric acid salt pH value regulator
Optical phenomenon, affects product quality.Additionally, oral liquid of the present invention is applicable to children, therefore, from the standpoint of mouthfeel, select citron
Acid sodium and citric acid, relative mouthfeel is easier to accept.
Further, described Linezolid oral administration mixed suspension also includes wetting agent, preservative, sweetener and flavouring;Described
Wetting agent is polysorbate, and described preservative is Sodium Benzoate, and described sweetener is sorbierite, and described flavouring is that cherry powder is fragrant
Essence.
Wetting agent in the present invention selects polyoxyethylene sorbitan monoleate, and polyoxyethylene sorbitan monoleate is nonionic surface active agent, Ke Yigai
The wetability of kind surface of drug particles, and the change of high concentration electrolyte and pH value is the least on impact.Linezolid microparticle surfaces
There is hydrophobicity, after being added in water, be suspended in water surface, it is difficult to be spontaneously wet out by water dispersion, therefore select polyoxyethylene sorbitan monoleate conduct
Wetting agent can reduce the interfacial tension of particulate and water very well, makes Linezolid particulate reach the purpose of effective wetting, and with profit how it
Azoles amine has good chemical compatibility, not with Linezolid generation chemical reaction.
Particulate chemistry stability is different, and the hydrophobic ability of microparticle surfaces is different, and particle size is different, inevitable Surfactant
Kind select different with consumption.As kinds of surfactants of the present invention selects polyoxyethylene sorbitan monoleate, it has good with Linezolid
Good chemical compatibility, not with Linezolid generation chemical reaction;Hydrophobic performance and present invention profit according further to Linezolid
How the particle size range of azoles amine particulate, selects the consumption of polyoxyethylene sorbitan monoleate, and hydrophobicity needs the most by force polyoxyethylene sorbitan monoleate consumption the biggest, particulate
The least, surface area is the biggest, and required polyoxyethylene sorbitan monoleate consumption is the biggest, and the present invention finally determines the use of polyoxyethylene sorbitan monoleate through screening
Amount.
The present invention is according to the bacteriostasis of Linezolid self and the bacteriostatic test of product oral liquid, and preservative finally selects
Sodium Benzoate and consumption thereof, can reach effective antiseptic effect, and have good physical chemistry compatibility with Linezolid, no
Understand product suspendible effect and content, have related substance to produce harmful effect.
The range of choice of oral liquid sweetener and flavouring is relatively wide, sweetener such as conventional Aspartame, saccharin sodium, trichlorine
Sucrose, honey element, Stevioside, essence etc..The present invention selects sorbierite can be effectively improved the mouthfeel of oral liquid, has refrigerant sense,
Being particularly suited for old man and children, compliance is preferable, and good with Linezolid chemical compatibility, the consumption of the sorbierite of selection
Optimal mouthfeel effect can be reached.The flavouring present invention selects U.S. kerry cherry powder essence, and mouthfeel is cherry-flavored, is particularly suited for
Through compatibility test, the mouthfeel of children, shows that this cherry powder essence and consumption thereof do not disturb oral liquid content of the present invention and relevant
The mensuration of material, good with Linezolid compatibility, do not affect its chemical stability.
Other more sweetener or flavourings in addition to sorbierite of the present invention, cherry powder, such as saccharin sodium, Aspartame, sweet
Honey element etc. is unfavorable for that in oral liquid, the stability of Linezolid maybe can be disturbed quality determining method content or have the mensuration of related substance,
Therefore the present invention optimal sweetener that finally selects sorbierite and cherry powder essence to be Linezolid oral liquid and flavouring.
Further, described Linezolid oral administration mixed suspension is the most composed of the following components: Linezolid 0.5~
2.0 parts, sodium carboxymethylcellulose 0.5~5.0 parts, polyoxyethylene sorbitan monoleate 0.05~0.5 part, sodium citrate 0.15~0.20 part, Chinese holly
Rafter acid 0.08~0.10 part, Sodium Benzoate 0.22~0.28 part, sorbierite 22~28 parts, cherry powder essence 1.2~1.8 parts and water
Medium.
Preferred as one, described Linezolid oral administration mixed suspension is the most composed of the following components: profit how azoles
Amine 0.5~2.0 parts, sodium carboxymethylcellulose 2.0~5.0 parts, polyoxyethylene sorbitan monoleate 0.2~0.4g part, sodium citrate 0.18 part,
Citric acid 0.09 part, preservative 0.25 part, sweetener 25 parts, flavouring 1.5 parts and aqueous medium.
The two of the purpose of the present invention are to provide the preparation method of a kind of Linezolid oral administration mixed suspension, including following step
Rapid:
1) sodium carboxymethylcellulose taking above-mentioned weight portion is dissolved in aqueous medium, obtains solution I after fully dissolving;
2) to step 1) described solution I adds the polyoxyethylene sorbitan monoleate of above-mentioned weight portion, stir molten clearly, obtain solution II;
3) to step 2) described solution II adds the Linezolid of above-mentioned weight portion, fully mix, flocculation, obtain suspension
Ⅲ;
4) to step 3) described suspension III adds sodium citrate and the citric acid of above-mentioned weight portion, regulate pH value,
Suspension IV;
5) to step 4) described suspension IV adds the preservative of above-mentioned weight portion, sweetener and flavouring, molten clear after
Obtain suspendible oral liquid finished product.
Further, step 1) the first dispersion in normal temperature purified water of described sodium carboxymethylcellulose, it is heated under stirring condition
80-100 DEG C of swelling clarification, is cooled to room temperature, obtains solution I.
Sodium carboxymethylcellulose is macromolecular compound, swelling relatively slow in cold water, and more than 80 DEG C can the most swelling be
Macromolecule glue liquid solution, and in 100 DEG C, this Polymer Solution is more stable, and auxiliary material degradation impurity peak will not occur.It is cooled to room
The purpose of temperature, follow-up addition polyoxyethylene sorbitan monoleate and the physical and chemical stability of Linezolid, make particulate preferably disperse
Flocculation, reaches optimal volume settling ratio.
Further, step 1) described sodium carboxymethylcellulose with the weight part ratio of aqueous medium is: 0.5~5.0:65~75.
Further, step 3) in Linezolid be Linezolid micro mist, in solution II, add Linezolid micro mist, homogeneous
Speed 5000~8000rpm dispersion 5~10min, mixing, flocculation, obtain suspension III.
Described homogeneous speed is key process parameter, it is necessary to have enough intensity to make Linezolid micro mist and polyoxyethylene sorbitan monoleate
It is fully contacted, reduces its microparticle surfaces tension force, reach the purpose of full and uniform dispersion, wetting.This processing step need to be with all
Carrying out in the jar of matter equipment, and homogeneous speed need to control within the scope of the invention, rotating speed is too low, and homogenizing time is too short, micro-
Grain does not reaches dispersion moistening effect;Rotating speed is excessive or homogenizing time is long, because containing polyoxyethylene sorbitan monoleate surface-active containing suspension
Agent, is easily generated a large amount of foam, is also unfavorable for the dispersion of particulate, soaks, flocculates.Though the present invention's is homogenizer, but this behaviour
Making to be not limited to homogenizer, every equipment that can produce acutely vibration all can realize the dispersion of particulate of the present invention, soak, wads a quilt with cotton
Solidifying, as used ultrasonic equipment, the mixing plant of bigger rotating speed power, magnetic stirring apparatus etc..Different pharmaceutical particulate, its superficiality
Matter different (as hydrophobicity is different), needed for prepare the supplementary product kind of suspension different (such as wetting agent and the kind of suspending agent and dense
Degree difference), suspension matrix is variant, necessarily causes corresponding homogeneous strength demand to change.As in the present invention 5000~
Needing homogeneous more than 5 minutes under 8000rpm homogeneous speed, preferably 5~10 minutes, under this intensity and time conditions, Linezolid was micro-
Grain ability is fully dispersed, wetting, and flocculation obtains product flocculating effect optimal, and constant product quality, long-term placement all will not occur
Caking phenomenon.
Further, step 4) described regulation pH value is 4.2~5.2.
In described preparation method, after Linezolid particulate adds flocculation, just add pH adjusting agent sodium citrate and citron
Acid is to regulate pH value to 4.2~5.2, it is therefore intended that make negative electrical charge homogeneous on Linezolid particulate band.Because of Linezolid particulate
Before feeding intake, solution contains only a kind of charged material of sodium carboxymethylcellulose, can only be with single electric charge after particulate feeds intake
Contact, so that microparticle surfaces all brings homogeneous electric charge.If pH adjusting agent sodium citrate is incorporated in advance with citric acid
In carboxymethylcellulose sodium solution, after dissolving, add Linezolid particulate;This technique, because sodium citrate and citric acid are inorganic
Salt, can will be completely dissociated as positive and negative charge in the solution, now puts into drug microparticles, and some particles can be positively charged than so, part
Electronegative, it is susceptible to attracting between the particulate of this belt transect positive and negative charge, thus affects product quality, long-term placement particulate is easy
Producing agglomeration problems, as in comparative example 3, product flocculating effect is poor, sedimentation volume ratio only has 0.90, and long-term 40 DEG C of product is put
Lump after putting June.Therefore preparation method of the present invention is first to throw Linezolid in the carboxymethylcellulose sodium solution of single electric charge
In so that it is disperse, homogeneous negative electrical charge on band, after flocculation completely, add pH value regulator sodium citrate and citric acid, be conducive to
Product flocculation is stable, does not lumps.
The present invention adds preservative sodium benzoate, sweetener sorbierite and flavouring cherry powder fragrant in the most backward suspension
Essence, purpose is as it was previously stated, also for avoiding inhomogenous positive and negative charge on Linezolid band, there is a natural attraction between the sexes in generation, and caking is existing
As, affect product quality.
The beneficial effects of the present invention is: it is stable that the Linezolid oral administration mixed suspension of the present invention has good physical chemistry
Property, sedimentation volume ratio is high, good fluidity, all good without caking phenomenon and other quality index, shows good quality of product;This
Bright preparation method shows through pilot scale and trial production amplification, and this technique is simple, feasible, and has reappearance, can be uniform
Produce the Linezolid oral administration mixed suspension of satisfactory quality.
1. the invention provides a kind of Linezolid new oral formulation, i.e. Linezolid oral administration mixed suspension, has filled up city
Field is blank (market only has tablet, parenteral solution), provides new formulation choosing for Grain-positive (G+) coccigenic infected patient
Select;Domestic having been carried out industrialization, price is relatively cheap, is truly realized super quality and competitive price, for this type of patient significantly reduce through
Ji burden.
2. the suspendible oral liquid that the present invention provides is a kind of rapid-action, and quality stability is good, without opalescence, does not lumps, produces
Product content, there is related substance stable, clinical safety and the good oral administration mixed suspension of curative effect.
3. the suspendible oral liquid that the present invention provides can provide the compliance of dysphagia patients significantly, it is simple to swallows and takes medicine,
Divided dose and correct dose are administered, and are particularly suited for children and gerontal patient.
4. the suspendible oral liquid carrying convenience of the present invention, the most accurate divided dose, be particularly suited for children and enter according to body weight
Row Linezolid is administered metering.
Detailed description of the invention
Hereinafter detailed description of a preferred embodiment of the present invention will be given.The reality of unreceipted actual conditions in preferred embodiment
Proved recipe method, generally according to normal condition, illustrated embodiment is to preferably illustrate present disclosure, but is not
Present disclosure is only limitted to illustrated embodiment.So those of ordinary skill in the art according to foregoing invention content to embodiment party
Case carries out nonessential improvement and adjustment, still falls within protection scope of the present invention.
Embodiment 1 Linezolid oral mixed suspension formula of liquid 1 and preparation method
(1) preparation prescription: (making 1000ml altogether)
(2) preparation method:
1) weigh 4/5 recipe quantity purified water, recipe quantity suspending agent sodium carboxymethylcellulose is added on wherein, is heated to 80-
100 DEG C, stir swelling clarification, be cooled to room temperature, obtain solution I;
2) in solution I add wetting agent polyoxyethylene sorbitan monoleate, stir molten clearly, obtain solution II;
3) adding Linezolid micro mist again in solution II, homogeneous 5000rpm disperses 5min, mixing, and flocculation obtains suspension
Ⅲ;
4) in suspension III, add pH adjusting agent sodium citrate and citric acid, obtain suspension IV;
5) the most backward suspension IV adds the preservative sodium benzoate of recipe quantity, sweetener sorbierite and flavouring cherry
Powder essence, 30Hz stirs 10min, molten clear after, mend and add water to 1000ml, obtain suspendible oral liquid finished product.
Embodiment 2 Linezolid oral mixed suspension formula of liquid 2 and preparation method
(1) preparation prescription: (making 1000ml altogether)
(2) preparation method:
1) weigh 4/5 recipe quantity purified water, recipe quantity suspending agent sodium carboxymethylcellulose is added on wherein, is heated to 80-
100 DEG C, stir swelling clarification, be cooled to room temperature, obtain solution I;
2) in solution I add wetting agent polyoxyethylene sorbitan monoleate, stir molten clearly, obtain solution II;
3) adding Linezolid micro mist again in solution II, homogeneous 5000rpm disperses 8min, mixing, and flocculation obtains suspension
Ⅲ;
4) in suspension III, add pH adjusting agent sodium citrate and citric acid, obtain suspension IV;
5) the most backward suspension IV adds the preservative sodium benzoate of recipe quantity, sweetener sorbierite and flavouring cherry
Powder essence, 30Hz stirs 10min, molten clear after, mend and add water to 1000ml, obtain suspendible oral liquid finished product.
Embodiment 3 Linezolid oral mixed suspension formula of liquid 3 and preparation method
(1) preparation prescription: (making 1000ml altogether)
(2) preparation method:
1) weigh 4/5 recipe quantity purified water, recipe quantity suspending agent sodium carboxymethylcellulose is added on wherein, is heated to 80-
100 DEG C, stir swelling clarification, be cooled to room temperature, obtain solution I;
2) in solution I add wetting agent polyoxyethylene sorbitan monoleate, stir molten clearly, obtain solution II;
3) adding Linezolid micro mist again in solution II, homogeneous 5000rpm disperses 8min, mixing, and flocculation obtains suspension
Ⅲ;
4) in suspension III, add pH adjusting agent sodium citrate and citric acid, obtain suspension IV;
5) the most backward suspension IV adds the preservative sodium benzoate of recipe quantity, sweetener sorbierite and flavouring cherry
Powder essence, 30Hz stirs 10min, molten clear after, mend and add water to 1000ml, obtain suspendible oral liquid finished product.
Embodiment 4 Linezolid oral mixed suspension formula of liquid 4 and preparation method
(1) preparation prescription: (making 1000ml altogether)
(2) preparation method:
1) weigh 4/5 recipe quantity purified water, recipe quantity suspending agent sodium carboxymethylcellulose is added on wherein, is heated to 80-
100 DEG C, stir swelling clarification, be cooled to room temperature, obtain solution I;
2) in solution I add wetting agent polyoxyethylene sorbitan monoleate, stir molten clearly, obtain solution II;
3) adding Linezolid micro mist again in solution II, homogeneous 5000rpm disperses 10min, mixing, and flocculation obtains suspension
Liquid III;
4) in suspension III, add pH adjusting agent sodium citrate and citric acid, obtain suspension IV;
5) the most backward suspension IV adds the preservative sodium benzoate of recipe quantity, sweetener sorbierite and flavouring cherry
Powder essence, 30Hz stirs 10min, molten clear after, mend and add water to 1000ml, obtain suspendible oral liquid finished product.
Embodiment 5 Linezolid oral mixed suspension formula of liquid 5 and preparation method
(1) preparation prescription: (making 1000ml altogether)
(2) preparation method:
1) weigh 4/5 recipe quantity purified water, recipe quantity suspending agent sodium carboxymethylcellulose is added on wherein, is heated to 80-
100 DEG C, stir swelling clarification, be cooled to room temperature, obtain solution I;
2) in solution I add wetting agent polyoxyethylene sorbitan monoleate, stir molten clearly, obtain solution II;
3) adding Linezolid micro mist again in solution II, homogeneous 5000rpm disperses 10min, mixing, and flocculation obtains suspension
Liquid III;
4) in suspension III, add pH adjusting agent sodium citrate and citric acid, obtain suspension IV;
5) the most backward suspension IV adds the preservative sodium benzoate of recipe quantity, sweetener sorbierite and flavouring cherry
Powder essence, 30Hz stirs 10min, molten clear after, mend and add water to 1000ml, obtain suspendible oral liquid finished product.
Embodiment 6 Linezolid oral mixed suspension formula of liquid 6 and preparation method
(1) preparation prescription: (making 1000ml altogether)
(2) preparation method:
1) weigh 4/5 recipe quantity purified water, recipe quantity suspending agent sodium carboxymethylcellulose is added on wherein, is heated to 80-
100 DEG C, stir swelling clarification, be cooled to room temperature, obtain solution I;
2) in solution I add wetting agent polyoxyethylene sorbitan monoleate, stir molten clearly, obtain solution II;
3) adding Linezolid micro mist again in solution II, homogeneous 5000rpm disperses 10min, mixing, and flocculation obtains suspension
Liquid III;
4) in suspension III, add pH adjusting agent sodium citrate and citric acid, obtain suspension IV;
5) the most backward suspension IV adds the preservative sodium benzoate of recipe quantity, sweetener sorbierite and flavouring cherry
Powder essence, 30Hz stirs 10min, molten clear after, mend and add water to 1000ml, obtain suspendible oral liquid finished product.
Embodiment 7 Linezolid oral mixed suspension formula of liquid 7 and preparation method
(1) preparation prescription: (making 1000ml altogether)
(2) preparation method:
1) weigh 4/5 recipe quantity purified water, recipe quantity suspending agent sodium carboxymethylcellulose is added on wherein, is heated to 80-
100 DEG C, stir swelling clarification, be cooled to room temperature, obtain solution I;
2) in solution I add wetting agent polyoxyethylene sorbitan monoleate, stir molten clearly, obtain solution II;
3) adding Linezolid micro mist again in solution II, homogeneous 5000rpm disperses 10min, mixing, and flocculation obtains suspension
Liquid III;
4) in suspension III, add pH adjusting agent sodium citrate and citric acid, obtain suspension IV;
5) the most backward suspension IV adds the preservative sodium benzoate of recipe quantity, sweetener sorbierite and flavouring cherry
Powder essence, 30Hz stirs 10min, molten clear after, mend and add water to 1000ml, obtain suspendible oral liquid finished product.
Comparative example 1
(1) preparation prescription: (making 1000ml altogether)
(2) preparation method:
1) weigh 4/5 recipe quantity purified water, recipe quantity suspending agent gelatin is added on wherein, add the swelling clarification of thermal agitation, cold
But to room temperature, solution I is obtained;
2) in solution I add wetting agent polyoxyethylene sorbitan monoleate, stir molten clearly, obtain solution II;
3) adding Linezolid micro mist again in solution II, homogeneous 4000rpm disperses 4min, mixing, and flocculation obtains suspension
Ⅲ;
4) in suspension III, add pH adjusting agent sodium citrate and citric acid, obtain suspension IV;
5) the most backward suspension IV adds the preservative sodium benzoate of recipe quantity, sweetener sorbierite and flavouring saccharin
Sodium, molten clear after, mend and add water to 1000ml, obtain suspendible oral liquid finished product.
Comparative example 2
(1) preparation prescription: (making 1000ml altogether)
(2) preparation method:
1) weigh 4/5 recipe quantity purified water, recipe quantity suspending agent sodium carboxymethylcellulose is added on wherein, is heated to 80-
100 DEG C, stir swelling clarification, be cooled to room temperature, obtain solution I;
2) in solution I add wetting agent polyoxyethylene sorbitan monoleate, stir molten clearly, obtain solution II;
3) adding Linezolid micro mist again in solution II, homogeneous 9000rpm disperses 11min, mixing, and flocculation obtains suspension
Liquid III;
4) in suspension III, add pH adjusting agent sodium citrate and citric acid, obtain suspension IV;
5) the most backward suspension IV adds the preservative sodium benzoate of recipe quantity, sweetener sorbierite and flavouring saccharin
Sodium, molten clear after, mend and add water to 1000ml, obtain suspendible oral liquid finished product.
Comparative example 3
(1) preparation prescription: (making 1000ml altogether)
(2) preparation method:
1) weigh 4/5 recipe quantity purified water, recipe quantity suspending agent sodium carboxymethylcellulose is heated to 80-100 DEG C, stirring
Swelling clarification, is cooled to room temperature, obtains solution I;
2) in solution I, add the wetting agent polyoxyethylene sorbitan monoleate of recipe quantity, pH adjusting agent sodium citrate and citric acid, anticorrosion
Agent Sodium Benzoate, sweetener sorbierite and flavouring cherry powder essence, stir molten clearly, obtain solution II;
3) adding Linezolid micro mist again in solution II, homogeneous 9000rpm disperses 11min, mixing, and water is added in flocculation
To 1000ml, obtain suspendible oral liquid finished product.
Embodiment 8 Linezolid oral administration mixed suspension product quality is identified
The Linezolid oral administration mixed suspension using the present composition and preparation method to prepare, has good physical chemistry
Stability, sedimentation volume ratio is high, good fluidity, all good without caking phenomenon and other quality index, shows good quality of product;
After 40 DEG C are accelerated to investigate June, product quality compared still without significant change with 0 day, again showed that constant product quality of the present invention
Well, superior in quality, specifically refer to table 5, table 6.
Table 50 day quality condition of Linezolid of the present invention oral administration mixed suspension
Table 6 Linezolid of the present invention oral administration mixed suspension accelerates quality condition after 40 DEG C of June
Sedimentation volume ratio assay method: with reference to " Chinese Pharmacopoeia " annex I in 2015, apparatus plug graduated cylinder measured embodiment sample
50ml, close plug, firmly shaking 1 minute, the beginning height Ho of record supensoid agent, after standing 3 hours, the sedimentation face of observation no longer changes
Time precipitum height H, its sedimentation volume ratio F be: F=H/Ho, concrete outcome is shown in Table 4.Evaluation mark according to oral administration mixed suspension
Standard, sedimentation volume ratio closer to 1, then shows that drug microparticles is uniformly dispersed, and flocculating effect is good, good quality of product.From table 4, table 5
In it can be seen that embodiment of the present invention sedimentation volume ratio has been all higher than 0.95, meet States Pharmacopoeia specifications and be not less than the requirement of 0.90, phase
To comparative example sedimentation volume ratio 0.75-0.90, product quality of the present invention is the most excellent.
Centrifuge-redisperse number of times: Example sample 25ml is as in 50ml tool plug centrifuge tube, 4000 revs/min, centrifugal
After 30min, take out, the fixing centrifugal mouth of pipe, then will be inverted bottom test tube, the most again along putting, come and go back and forth, be counted as 1 time, until
Micro-filtration cake is completely dispersed flocculation, record dispersion used number of times again, and evaluates the redispersibility of product with it.Centrifugal dispersion number of times
The fewest, show that product particles flocculate is effective, prevented from caking between particulate.From table 4, table 5 it can be seen that the embodiment of the present invention from
Heart dispersion number of times is respectively less than 15 times, 20-28 number of relative contrast's embodiment Centrifugal dispersion, hence it is evident that number of times is few.Separately add through 40 DEG C
Speed test understands, and all without caking phenomenon after embodiment of the present invention product high temperature 40 DEG C storage June, and comparative example all occurs in that
Caking, therefore product quality of the present invention is substantially better than comparative example.
Content assaying method: HPLC method, octadecyl silane is filler, YMC ODS-A4.6 × 150mm 3 μm;
UV detector: 254nm;Column temperature: 25 DEG C;Sampling volume: 10 μ l;Mobile phase A: trifluoroacetic acid aqueous solution (takes 10%
Trifluoroacetic acid solution 9ml joins 1000ml water);Mobile phase B: trifluoracetic acid acetonitrile solution (takes 10% trifluoroacetic acid solution 9ml
Join in 1000ml acetonitrile);Flow velocity: 1.0ml/min.Precision measures this product 5ml, puts in 100ml measuring bottle, adds 10% acetonitrile molten
Liquid is diluted to scale, shakes up, and precision measures 10 μ l and injects liquid chromatograph, records chromatogram;Another precision weighs Linezolid pair
According to product 10mg, it is placed in 100ml measuring bottle, dissolves with 10% acetonitrile solution and be diluted to scale, shaking up, as reference substance solution,
It is measured in the same method, calculates the content of Linezolid (C16H20FN3O4) in test sample by external standard method.Embodiment of the present invention stable content
Property good, 40 DEG C are accelerated content in June and 0 day without significant change, and comparative example 1, and content is decreased obviously.
Relevant substance-measuring method: inspection method HPLC method;Operation time 43min;Chromatographic condition and system suitability are same
Containing under quantifier;Take the test sample storing solution under assay item as need testing solution;It is right that precision measures under assay item
According to product solution 1ml, put in 100ml measuring bottle, by 10% dilution in acetonitrile to scale, shake up, as contrast solution.According to assay item
Under chromatographic condition, take contrast solution 10 μ l inject liquid chromatograph, regulate detector sensitivity, make the peak height at principal component peak about
For the 20%~25% of full scale, precision measures need testing solution and each 10 μ l of contrast solution, is injected separately in liquid chromatograph,
Record chromatogram.If any impurity peaks in test sample, calculating by the external standard method of the correction up factor, single impurity peak area cannot be greater than
2 times (0.2%) of contrast solution main peak area, each impurity peak area and cannot be greater than 5 times of contrast solution main peak area
(0.5%).The relevant material stability of the embodiment of the present invention is good, and 40 DEG C are accelerated content in June and 0 day without significant change, and contrast
Embodiment 1, has related substance substantially to increase.
Finally illustrating, above example is only in order to illustrate technical scheme and unrestricted, although with reference to relatively
The present invention has been described in detail by good embodiment, it will be understood by those within the art that, can be to the skill of the present invention
Art scheme is modified or equivalent, and without deviating from objective and the scope of technical solution of the present invention, it all should be contained at this
In the middle of the right of invention.
Claims (10)
1. Linezolid oral administration mixed suspension, it is characterised in that include following components in parts by weight: Linezolid 0.5~2.0
Part, sodium carboxymethylcellulose 0.5~5.0 parts, pH combination conditioning agent 0.23~0.30 part and aqueous medium.
Linezolid oral administration mixed suspension the most according to claim 1, it is characterised in that described Linezolid oral administration mixed suspension
Middle Linezolid particle size D90 is 10~150 μm.
Linezolid oral administration mixed suspension the most according to claim 1, it is characterised in that described Linezolid oral administration mixed suspension
PH value be 4.2~5.2.
Linezolid oral administration mixed suspension the most according to claim 1, it is characterised in that described pH combination conditioning agent specifically becomes
Be divided into the sodium citrate and citric acid, described sodium citrate with the weight part ratio of described citric acid to be: 0.15~0.20:0.08~
0.10。
Linezolid oral administration mixed suspension the most according to claim 1, it is characterised in that described Linezolid oral administration mixed suspension
Also include wetting agent, preservative, sweetener and flavouring;Described wetting agent is polysorbate, and described preservative is Sodium Benzoate,
Described sweetener is sorbierite, and described flavouring is cherry powder essence.
6. according to the Linezolid oral administration mixed suspension described in claim 1-5, it is characterised in that in parts by weight by following group
It is grouped into: Linezolid 0.5~2.0 parts, sodium carboxymethylcellulose 0.5~5.0 parts, polyoxyethylene sorbitan monoleate 0.05~0.5 part, Chinese holly
Rafter acid sodium 0.15~0.20 part, citric acid 0.08~0.10 part, Sodium Benzoate 0.22~0.28 part, sorbierite 22~28 parts, cherry
Peach powder essence 1.2~1.8 parts and aqueous medium.
7. the preparation method of Linezolid oral administration mixed suspension, it is characterised in that comprise the following steps:
1) sodium carboxymethylcellulose taking above-mentioned weight portion is dissolved in aqueous medium, obtains solution I after fully dissolving;
2) to step 1) described solution I adds the polyoxyethylene sorbitan monoleate of above-mentioned weight portion, stir molten clearly, obtain solution II;
3) to step 2) described solution II adds the Linezolid of above-mentioned weight portion, fully mix, flocculation, obtain suspension III;
4) to step 3) described suspension III adds sodium citrate and the citric acid of above-mentioned weight portion, regulate pH value, obtain suspendible
Liquid IV;
5) to step 4) described suspension IV adds the preservative of above-mentioned weight portion, sweetener and flavouring, molten clear after and get final product
Suspendible oral liquid finished product.
Preparation method the most according to claim 7, it is characterised in that step 1) described sodium carboxymethylcellulose is first at normal temperature
Purified water is disperseed, is heated to 80-100 DEG C of swelling clarification under stirring condition, is cooled to room temperature, obtain solution I.
Preparation method the most according to claim 7, it is characterised in that step 1) described sodium carboxymethylcellulose and aqueous medium
Weight part ratio be: 0.5~5.0:65~75.
Preparation method the most according to claim 7, it is characterised in that step 3) in Linezolid be Linezolid micro mist,
In solution II, add Linezolid micro mist, homogeneous speed 5000~8000rpm dispersion 5~10min, mixing, flocculation, obtain suspension
Liquid III.
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CN111728944A (en) * | 2020-06-28 | 2020-10-02 | 山东达因海洋生物制药股份有限公司 | Linezolid dry suspension and preparation method thereof |
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CN107595782A (en) * | 2017-05-18 | 2018-01-19 | 广州大光制药有限公司 | A kind of Linezolid dry suspensoid agent and preparation method thereof |
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CN111728944A (en) * | 2020-06-28 | 2020-10-02 | 山东达因海洋生物制药股份有限公司 | Linezolid dry suspension and preparation method thereof |
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