CN105663038B - A kind of liquid slow-release preparation and preparation method thereof - Google Patents
A kind of liquid slow-release preparation and preparation method thereof Download PDFInfo
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- CN105663038B CN105663038B CN201610076087.XA CN201610076087A CN105663038B CN 105663038 B CN105663038 B CN 105663038B CN 201610076087 A CN201610076087 A CN 201610076087A CN 105663038 B CN105663038 B CN 105663038B
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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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
Abstract
The invention discloses a kind of sustained release preparation and preparation method thereof containing ion exchange resin and hydrophilic gel, sustained release preparation is made of drug-ion exchange resin complexes and suspension base, wherein, drug-ion exchange resin complexes are by can further contain insoluble polymer and plasticizer with active medicine, the pharmaceutically acceptable ion exchange resin in conjunction with ion exchange resin, drug-ion exchange resin complexes；Suspension matrix is made of hydrophilic gel, acid regulator, thickener, preservative, antioxidant, wetting agent, colorant, sweetener.
Description
Technical field
The invention belongs to pharmaceutical technology fields, delay more particularly to a kind of containing ion exchange resin and the oral of hydrophilic gel
Release suspension and preparation method thereof.
Background technique
In recent years, with the development of the deep progress and polymer material science of drug delivery system theoretical research, drug delivery
Systematic research all increases constantly from kind to dosage form.Although oral sustained release solid pharmaceutical preparation effectively can delay drug in body
Interior absorption, to keep blood concentration steady, side effect is reduced, and validity, safety and the compliance of medication of drug obtain
Improve.But oral sustained release solid pharmaceutical preparation depends on functional slow-release material to have certain shapes more, it is not possible to break into two with one's hands or grind
At taking after fine powder, it is unsuitable for being suitable for the patient of the dysphagias such as children and the elderly, therefore develop liquid slow-release preparation ten
Divide necessity.Oral sustained release suspension is made of as a kind of liquid preparation sustained-release microparticle and suspension base two parts, as one
Multiple-unit delivery system has the advantage that particle composition of the 1, slow-releasing system there are many slow release drug, can release the drug
Steadily；2, convenient for oral, the children and old man of particularly suitable dysphagia improve drug compliance；3, preparation granularity very little, can
Reduce to GI irritation, and physiological disposition influenced by gastric emptying it is small；4, it is easy to the spy that divided dose is taken with liquid preparation
Point, dosage are accurate；5, adjustable good mouthfeel, is easily received by children and old man.As it can be seen that oral sustained release suspension is in youngster
Child's administration and disease of old people medication have a very important significance.
Liquid slow-release preparation depends on ion exchange resin to realize more at present, in the solution can be by itself ion and solution
In same sex ion swap.The physical property of ion exchange resin itself can meet the needs of preparation, can also be
Do not change and ion-exchange reactions occurs with drug on the basis of pharmaceutical activity forms drug-resin complex.This compound only has
In the case where there is corresponding extraneous ion, drug can be just replaced, and be discharged again, so that Drug controlled release is played, without
It is influenced by the volume of the pH value of enteron aisle, enzymatic activity and gastro-intestinal Fluid.It is currently used sustained release compound resin be resin carry medicine after answer
It closes object and needs further to coat slow-release material to reach sustained release purpose, commonly using preparation method is fluidized bed powder coating method, emulsification
Solvent coating method.As Chinese patent CN101400343B, CN102488652B, CN103860464A, CN104306330A,
Sustained release liquid formulations disclosed in CN1820752A etc. and preparation method thereof, in preparation method sustained release performance mainly by adjusting
The thickness of coating membrane controls release time of drug, and coating process is completed by fluidized bed powder coating.But
Since drug-resin complex belongs to subparticle, usual granularity is usually more demanding to coating equipment in sugar production line less than 100 μm, and by
In needing to wrap up a large amount of slow-release material that increases weight, yield is lower in production, poor reproducibility between batch；Chinese patent CN1546008
A kind of liquid slow-release preparation of ambroxol hydrochloride is provided, the method being coated using emulsified solvent is needed repeatedly to impregnate, uses third
Organic solvents such as ketone, ethyl alcohol, petroleum ether and process is many and diverse, and sustained-release microparticle extends at any time in suspension the case where leakage
It is more.It develops a kind of effectively suitable for the very urgent of the liquid slow-release preparation of industrialized production.
The present invention provides a kind of liquid slow-release preparation, conjunctive use ion exchange resin, insoluble polymer and hydrophilic
Whole or several combinations of the multiple slow controlled release mechanism of glue achieve the effect that stable slow release drug.Only by impregnating,
It is dry, it is scattered in the suspension medium containing hydrophilic gel and reaches stable slow release effect, do not use organic solvent.Mesh of the invention
Be a kind of stable liquid slow-release preparation is provided, preparation process is simple, keep preparation process easily controllable, favorable reproducibility, behaviour
The property made is strong, and drug high income, reduces the difficulty and production cost of industrialization production.
Summary of the invention
Inventor provides a kind of oral sustained release suspension and its preparation process containing ion exchange resin and hydrophilic gel, can
Not need particle coating or dipping granulation, to solve to be coated poor reproducibility, industrialization difficulty, medicine in existing particle packaging technique
The problems such as object yield is low, using organic solvent.
For this purpose, the present invention provides a kind of sustained release preparation, by drug-ion exchange resin complexes and suspension matrix system
At, wherein the drug-ion exchange resin complexes are made of drug, pharmaceutically acceptable ion exchange resin, or by
Drug, pharmaceutically acceptable ion exchange resin, polymer and plasticizer are made；Drug-ion exchange resin complexes and
The weight ratio of suspension matrix is 0.001~0.1:1, wherein the ion exchange resin is amberlite not soluble in water
Rouge, selected from pharmacologically inert organic and/or inorganic matrix, it includes functional group that is ionic or being ionized, organic groups
Matter is synthesis or partially synthetic；Inorganic matrix includes the silica gel that addition ionic group is modified；The weight of itself and drug
Amount ratio is 0.05~20:1, and hydrophilic gel is contained in the suspension base, and hydrophilic gel is selected from: xanthan gum, tragacanth, carbomer,
Guar gum, gum arabic, pectin, gelatin, dosage are the 0.1%~1% of suspension matrix weight.
Wherein, the ion exchange resin is selected from strong acid Na+Type IRP69 resin, weak acid H+Type IRP64 resin and weak acid K+
Type IRP188 resin also contains auxiliary material in the suspension matrix, is selected from: acid regulator, thickener, preservative, antioxidant,
Wetting agent, colorant, sweetener；The polymer is selected from: polyvinyl acetate polymer, methylcellulose, cellulose nitrate
Element, polyvinyl chloride, cellulose acetate, acrylic acid based polymer, polymer solids level are the 10% of drug-ion exchange resin amount
~80%, the plasticizer is selected from: glyceryl triacetate, dibutyl sebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol, lemon
Lemon triethylenetetraminehexaacetic acid ester, CitroflexA-2, citroflex A-4, tributyl citrate, triacetin, Sai Lufei P,
Plasticizer consumption is the 2%~15% of polymer volume.
Sustained release preparation of the invention is formulated as follows: drug 0.001%~8%, ion exchange resin 0.02%~10%,
Hydrophilic gel 0.1%~1%, remaining is auxiliary material and water.
Preferably, sustained release preparation of the invention is formulated as follows: drug 0.05%~5%, and ion exchange resin 0.05%~
8%, hydrophilic gel 0.2%~0.8%, acid regulator 0.05%~0.7%, thickener 3%~50%, preservative 0.01%~
0.2%, antioxidant 0.01%~0.1%, wetting agent 0.05%~2.5%, colorant 0.0005%~0.02%, sweetener
2%~50%, remaining is water.
It is furthermore preferred that sustained release preparation of the invention, is formulated as follows: drug 0.05%~2%, ion exchange resin 0.05%
~5%, hydrophilic gel 0.2%~0.5%, acid regulator 0.1%~0.5%, thickener 10%~40%, preservative 0.01%
~0.2%, antioxidant 0.02%~0.08%, wetting agent 0.05%~1%, colorant 0.0005%~0.02%, sweetener
5%~30%, remaining is water.
Ion exchange resin of the present invention has effects that the acceptable ion exchanger resin of the present invention selected from any one,
It is preferred that strong acid Na+Type IRP69 resin, weak acid H+Type IRP64 resin and weak acid K+Type IRP188 resin, most preferably are as follows:
AmberliteTMIRP-69 resin.
Wherein, polymer and plasticizer can be contained in the drug-ion exchange resin complexes.
Wherein, the polymer is selected from: polyvinyl acetate polymer, methylcellulose, nitrocellulose, polychlorostyrene second
Alkene, cellulose acetate, acrylic acid based polymer, polymer solids level are 10%~80% (w/ of drug-ion exchange resin amount
W),
Wherein, the plasticizer is selected from: glyceryl triacetate, dibutyl sebacate, propylene glycol, polyethylene glycol, poly- second
Enol, triethyl citrate, CitroflexA-2, citroflex A-4, tributyl citrate, triacetin,
Sai Lufei P, plasticizer consumption are 2%~15% (w/w) of polymer volume.
Contain hydrophilic gel in suspension base of the present invention, hydrophilic gel is selected from: xanthan gum, tragacanth, carbomer, Guar
Glue, gum arabic, pectin, gelatin.
Can be also added as needed in suspension matrix acid regulator, thickener, preservative, antioxidant, wetting agent,
Toner, sweetener etc..
In suspension matrix, the weight ratio of hydrophilic gel is 0.1%~1%, remaining is solvent, such as water, ethyl alcohol etc..
Acid regulator, thickener, preservative, antioxidant, wetting agent, colorant, sweetener can be added as needed
Deng, wherein weight ratio of each component in suspension matrix are as follows: acid regulator 0.05%~0.7%, thickener 3%~
50%, preservative 0.01%~0.2%, antioxidant 0.01%~0.1%, wetting agent 0.05%~2.5%, colorant
0.0005%~0.02%, sweetener 2%~50%.
Drug of the present invention is selected from: clonidine, carbinoxamine, ambroxol, hydrocodone, pseudoephedrine, methylphenidate, the right side
Revolve methylphenidate, diphenhydramine, carbamazepine, Oxymorphone, brufen, morphine, codeine, C16H25NO2, neo-synephrine,
Venlafaxine, oxybutynin, melbine, dexchlorpheniramine, fexofenadine, phenylpropanolamine, chlorphenamine, amphetamine,
Naproxen, Diclofenac, Paxil, Amoxicillin or their pharmaceutically acceptable salts.
In the present invention, the weight ratio of drug-ion exchange resin complexes and suspension matrix is 0.001~0.1:1,
In drug-ion exchange resin complexes, the weight ratio of drug and ion exchange resin is 0.01~4:1, and polymer is in medicine
Weight ratio in object-ion exchange resin complexes is 0.1~0.8:1, and plasticizer is in drug-ion exchange resin complexes
In weight ratio be 0.002~0.125:1.
The present invention further provides the preparation methods of preparation of the present invention, which comprises the steps of:
Step 1, the preparation of drug-ion exchange resin complexes:
It is dried after drug and ion exchange resin are carried out load medicine, sieving, or drug and ion exchange resin is carried
Polymer and plasticizer mixing granulation are added after medicine, is sieved after dry；
Step 2, the preparation of the drug-resin complex of dipping:
Plasticizer is dissolved in polymer, is added in drug-ion exchange resin complexes, is stirred, is sheared, granulation,
Whole grain, the drug-resin complex impregnated；
Step 3, the preparation of suspension base:
Hydrophilic gel, acid regulator, thickener, preservative, antioxidant, wetting agent, colorant, sweetener are divided in water
It dissipates uniformly, obtains suspension base；
Step 4, the preparation of suspension:
It disperses the drug-resin complex for the dipping that step 2 obtains in suspension base.
Preferably, preparation method of the invention, which comprises the steps of:
Step 1, the preparation of drug-ion exchange resin complexes: drug is dissolved in a certain amount of deionized water, is being stirred
Under the conditions of mixing, the ion exchange resin of recipe quantity is added, under the conditions of 25 DEG C~60 DEG C, stirs 1~12h, it is quiet after mixing completely
It sets or filters, remove supernatant, repeat to be beaten 1~4 time with the deionized water of sufficient amount, wash away unbonded free drug, do
It is dry, by the moisture drying of drug-resin complex to 2%~30%, obtain drug-ion exchange resin complexes；
Step 2, the preparation of the drug-resin complex of dipping:
Plasticizer is dissolved in polymer, the drug-resin complex to get impregnating agent, prepared by step 1 is stirred evenly
It is placed in wet granulator, impregnating agent is added, stir, shear, granulation, extremely by the dry moisture of the drug-resin complex of dipping
2%~5%, whole grain, repeated impregnations step, until impregnating agent is all added, the drug-resin complex impregnated；
Step 3, the preparation of suspension:
Hydrophilic gel, acid regulator, thickener, preservative, antioxidant, wetting agent, colorant, sweetener are divided in water
It dissipates uniformly, obtains premix matrix, pharmaceutical-impregnated-resin complexes that step 2 is obtained are mixed with wetting agent, are added to above-mentioned pre-
In mixed radix matter, water is added to adjust volume, is uniformly mixed, obtains suspension.
Preparation method of the present invention, which is characterized in that the drug is selected from: clonidine, carbinoxamine, ammonia bromine
Rope, hydrocodone, pseudoephedrine, methylphenidate, dextrorotation methylphenidate, diphenhydramine, carbamazepine, Oxymorphone, brufen,
Coffee, codeine, C16H25NO2, neo-synephrine, Venlafaxine, oxybutynin, melbine, dexchlorpheniramine, Fexofenadine
Fixed, phenylpropanolamine, chlorphenamine, amphetamine, naproxen, Diclofenac, Paxil, Amoxicillin or they pharmaceutically
Acceptable salt.
The polymer is selected from: polyvinyl acetate polymer, methylcellulose, nitrocellulose, polyvinyl chloride, vinegar
Acid cellulose, acrylic acid based polymer, polymer solids level are 10%~80% (w/w) of drug-ion exchange resin amount, institute
The plasticizer stated is selected from: glyceryl triacetate, dibutyl sebacate, propylene glycol, polyethylene glycol, polyvinyl alcohol, lemon triethylenetetraminehexaacetic acid
Ester, CitroflexA-2, citroflex A-4, tributyl citrate, triacetin, Sai Lufei P, plasticizer are used
Amount is 2%~15% (w/w) of polymer volume.
Ion exchange resin of the invention is ion exchange resin not soluble in water, preferably pharmacologically inert organic
And/or electrodeless matrix, it includes for functional group that is ionic or being ionized under pH environment appropriate.Organic substrate can be with
Be synthesis (such as: acrylic acid, methacrylic acid, sulfonated phenylethylene, sulfonated divinyl benzene polymer or copolymer) or portion
Division at (such as: modified cellulose and glucan).Inorganic matrix is preferably comprised to be carried out by addition ionic group
The silica gel of modification.Covalently bound group can be highly acid (such as: sulfonic acid, phosphoric acid), weak acid (such as: carboxylic acid), highly basic (example
Such as: primary amine), weak base (such as: quaternary ammonium) or acid and basic group combination.Ion exchange resin used at present is nearly all
It is the Spherical copolymer with certain degree of cross linking, has the resin of over one hundred kind of different brands, U.S. FDA approved in the world
The pharmaceutical grade ion exchange resin of Rohm&Hass company lists, and has been embodied in United States Pharmacopeia 23 editions, such as strong acid Na+Type
IRP69 resin, weak acid H+Type IRP64 resin and weak acid K+Type IRP188 resin etc..
The preferred propylene glycol of the plasticizer, triethyl citrate and triacetin.
The plasticizer consumption accounts for 2%~15% (w/w) of insoluble polymer solid content.
Hydrophilic gel is xanthan gum, tragacanth, carbomer, guar gum, gum arabic, fruit in the suspension base
One or more of glue, gelatin, preferably xanthan gum, dosage are 0.2%~0.5%.
[compared with prior art, the technology bring benefit]
Compared with prior art, oral sustained release suspension of the invention has the following technical effect that
(1) present invention in drug-ion exchange resin complexes by being added sustained-release matrix material, by insoluble poly-
The retardation for closing object effectively reduces the peak concentration of drug after taking and improves medicine-valley concentration, and reaching both will not be dense because of medicine peak
Spending height leads to side effect, also avoids that the effect of therapeutic effect drawback cannot be played because drug concentration is too low.
(2) present invention prepares drug-resin complex by carrying medicine and two steps of dipping, is not necessarily to through fluidized bed to powder bag
Clothing and prolonged heat treatment for solidification, making coating, energy consumption is lower completely, is also conducive to amplification production and quality control.
(3) one or more hydrophilic gels are added in the present invention in suspension base, on the one hand, utilize the mucosa adhesion of hydrophilic gel
Property extends drug-resin complex in the retention time of gastrointestinal tract；On the other hand, using the network structure of hydrophilic gel, into one
Release of the step control drug after taking in 0-6h.
The present invention controls drug releasing in the gastrointestinal tract by ion exchange resin, insoluble polymer and hydrophilic gel
It puts, achievees the purpose that stable blood concentration.The invention also discloses a kind of preparation method of sustained release preparation, the present invention only passes through leaching
Stain reaches slow release effect identical with fluidized bed coating, simplifies preparation process, keeps preparation process easily controllable, favorable reproducibility,
Strong operability, and drug high income reduce the difficulty and production cost of industrialization production.
Detailed description of the invention
The dipping carbinoxamine maleate oral sustained release suspension and embodiment 10 of Fig. 1 embodiment 9 are coated maleic acid card ratio
Drug release rate of the husky bright oral sustained release suspension in 0.4mol/L potassium dihydrogen phosphate 12h
Specific embodiment
Below by way of the description of specific embodiment, invention is further described in detail, but this cannot be used for limiting this
The protection scope of invention, those skilled in the art's basic thought according to the present invention, can make various modifications or improvement, still
As long as they do not deviate from the basic of the present invention, it is all within the scope of the present invention.
[embodiment 1] ambroxol hydrochloride-resin complexes preparation
(1) 400g ambroxol hydrochloride is dissolved in 4L deionized water；(2) it is slowly added to 8000g under continuous mixing
AmberliteTMIRP-69 resin continuously stirs 12h at 50 DEG C, stands, incline supernatant, obtains drug-resin complex；
(3) 4L deionized water is added into the drug-resin complex that (2) obtain, stirs 10min, washes away unbonded free drug,
It stands, incline supernatant；Step (3) are repeated to operate 2 times；It is (4) (3) resulting drug-resin complex is dry at 60 DEG C,
Up to drug-resin complex.
Acyclovir-resin complexes preparation of [embodiment 2] dipping
(1) 140g acyclovir is dissolved in 20L 0.01mol/L hydrochloric acid solution；(2) slowly add under continuous mixing
Enter 1400g JK006 ion exchange resin, at 25 DEG C, continuously stir 8h, stands, incline supernatant, and it is compound to obtain drug-resin
Object；(3) 20L deionized water is added into the drug-resin complex that (2) obtain, stirs 30min, washes away unbonded dissociate
Drug is stood, and incline supernatant；Step (3) are repeated to operate 4 times；(4) by (3) resulting drug-resin complex at 60 DEG C
Drying to water content is 20%；(5) 2.6g triacetin is added in 165g Kollicoat SR 30D polymer, is stirred at room temperature
1h obtains impregnating agent；(6) drug-resin complex obtained by step (4) is placed in wet granulator, 167.6g impregnating agent is added
Enter in drug-resin complex, stirs, shearing, to form homogeneous material；(7) pharmaceutical-impregnated-resin obtained by step (6) is multiple
Close object at 60 DEG C dry to water content be 5% to get dipping drug-resin complex.
Topiramate-resin complexes preparation of [embodiment 3] dipping
(1) 200g Topiramate is dissolved in 40L deionized water；(2) it is slowly added to 10g under continuous mixing
AmberliteTMIRP-69 ion exchange resin continuously stirs 2h at 40 DEG C, stands, incline supernatant, obtains drug-resin
Compound；(3) 40L deionized water is added into the drug-resin complex that (2) obtain, stirs 30min, washes away unbonded
Free drug is stood, and incline supernatant；Step (3) are repeated to operate 3 times；(4) by (3) resulting drug-resin complex in 40
Being dried at DEG C to water content is 3%；(5) 5.3g triacetin is added in 334g Kollicoat SR 30D polymer, room temperature is stirred
1h is mixed, impregnating agent is obtained；(6) drug-resin complex obtained by step (4) is placed in wet granulator, 340g impregnating agent is added
Enter in drug-resin complex, stirs, shearing, to form homogeneous material；(7) pharmaceutical-impregnated-resin obtained by step (6) is multiple
Close object at 40 DEG C dry to water content be 5% to get dipping drug-resin complex.
Carbinoxamine maleate-resin complexes preparation of [experimental example 4] dipping
(1) 640g carbinoxamine maleate is dissolved in 8L deionized water；(2) it is slowly added under continuous mixing
2560g AmberliteTMIRP-69 resin continuously stirs 6h at 30 DEG C, stands, and incline supernatant, and it is multiple to obtain drug-resin
Close object；(3) 8L deionized water is added into the drug-resin complex that (2) obtain, stirs 5min, washes away unbonded dissociate
Drug is stood, and incline supernatant；Step (3) are repeated to operate 3 times；(4) by (3) resulting drug-resin complex at 50 DEG C
Drying to water content is 5%；(5) 135g 1,2-PD is added in 22000g Kollicoat SR 30D polymer, room
Temperature stirring 1h, obtains impregnating agent；(6) drug-resin complex obtained by step (4) is placed in wet granulator, 2370g is impregnated
Agent is added in drug-resin complex, stirs, shearing, to form homogeneous material；(7) by pharmaceutical-impregnated-tree obtained by step (6)
It is 5% that fat complexes, which are dried at 50 DEG C to water content, and repetition step (6) operation 2 times compound to get the drug-resin of dipping
Object.
Carbinoxamine maleate-resin complexes preparation of [embodiment 5] coating
(1) 640g carbinoxamine maleate is dissolved in 8L deionized water；(2) it is slowly added under continuous mixing
2560g AmberliteTM IRP-69 resin continuously stirs 6h at 30 DEG C, stands, incline supernatant, obtains drug-resin
Compound；(3) 8L deionized water is added into the drug-resin complex that (2) obtain, stirs 5min, washes away unbonded trip
From drug, stand, incline supernatant；Step (3) are repeated to operate 3 times；(4) by (3) resulting drug-resin complex in 50 DEG C
Lower drying to water content is 25%；(5) drug-resin complex obtained by step (4) is placed in wet granulator, by 2670g
Kollicoat SR 30D polymer is added in drug-resin complex, stirs, shearing, to form homogeneous material；It (6) will step
Suddenly pharmaceutical-impregnated-resin complexes obtained by (5) cross 40 meshes, dried at 50 DEG C to water content be 3% to get dipping medicine
Object-resin complexes；(7) by 79g 1,2- propylene glycol, 5000g Kollicoat SR 30D polymer be dispersed in 2421g go from
In sub- water, 1h is stirred at room temperature, obtains coating solution；(8) by the drug-resin complex impregnated obtained by step (6) cross respectively 40 mesh,
120 meshes take the drug-resin complex between 40-120 mesh to be placed in fluidized-bed coating machine, are coated, and weight increases
50%, coating conditions are as follows: 50-60 DEG C of inlet air temperature, 30-35 DEG C of temperature of charge, air velocity 40cfm, and atomization air pressure
3.0kg/cm2 is coated flow velocity 5g/min；(9) the resulting coating sample of step (8) is solidified into 12h in 50 DEG C to get coating
Carbinoxamine maleate-resin complexes.
The preparation of [embodiment 6] ambroxol hydrochloride oral slow-release suspension
(1) 14g anhydrous citric acid is dissolved in the deionized water of 500g, addition 200g sucrose, after stirring and dissolving, is added
800g maltodextrin, stirring, makes it completely dissolved, this is main solution；(2) in another container, 100g glycerol is added and adds
Then 3.6g methyl p-hydroxybenzoate and 0.4g propylparaben is added to 49 DEG C in heat, stirring keeps it completely molten
Solution；(3) solution prepared by step (2) is cooled to room temperature, and 4g xanthan gum is added slowly in solution to be formed uniformly
Dispersion liquid, stirring, makes it be uniformly dispersed, this is colloidal solution；(4) colloidal solution is added to main solution under stirring conditions
In, stirring is for 24 hours；(5) sodium pyrosulfite of 0.1g is dissolved with the deionized water of 5g, main solution is added；(6) 5g deionized water is used
0.032g lemon yellow and 0.072g famille rose are dissolved, main solution is added；(7) 2g strawberry and flavoring banana essence is added, uses deionization
Water is adjusted to final volume 1742mL, is uniformly mixed to get premix matrix；(8) by ambroxol hydrochloride-resin complexes and 1.1g
Polyoxyethylene sorbitan monoleate mixing, is added in above-mentioned premix matrix, and deionized water is added and is adjusted to 2000mL, is uniformly mixed, is mixed
Suspension.
The preparation of [embodiment 7] acyclovir oral sustained release suspension
(1) 8g tartaric acid is dissolved in the deionized water of 1000g, addition 2500g sucrose, after stirring and dissolving, is added
150g high-fructose corn syrup, stirring, makes it completely dissolved, this is main solution；(2) in another container, it is sweet that 400g is added
Oil is simultaneously heated to 49 DEG C, and 7.2g methyl p-hydroxybenzoate and 0.8g propylparaben is then added, and stirring keeps its complete
Fully dissolved；(3) solution prepared by step (2) is cooled to room temperature, and 25g xanthan gum is added slowly in solution to be formed
Even dispersion liquid, stirring, makes it be uniformly dispersed, this is colloidal solution；(4) colloidal solution is added to master under stirring conditions
In solution, stirring is for 24 hours；(5) sodium metabisulfite of 5g is dissolved with the deionized water of 100g, main solution is added；(6) 10g is used
Deionized water dissolves 0.064g lemon yellow and 0.144g famille rose, and main solution is added；(7) 4g strawberry and flavoring banana essence is added,
It is adjusted to final volume 3484mL with deionized water, is uniformly mixed to get premix matrix；(8) dipping acyclovir-resin is multiple
It closes object to mix with 125g polyoxyethylene sorbitan monoleate, be added in above-mentioned premix matrix, deionized water is added and is adjusted to 5000mL, mixing is equal
It is even, obtain suspension.
The preparation of [embodiment 8] Topiramate oral sustained release suspension
(1) 0.25g anhydrous citric acid is dissolved in the deionized water of 200g, addition 10g glucose, after stirring and dissolving,
250g high-fructose corn syrup is added, stirring makes it completely dissolved, this is main solution；(2) in another container, 30g is added
Glycerol is simultaneously heated to 49 DEG C, and 0.9g methyl p-hydroxybenzoate and 0.1g propylparaben is then added, and stirring makes it
It is completely dissolved；(3) solution prepared by step (2) is cooled to room temperature, and 5g carbomer is added slowly in solution to be formed
Uniform dispersion liquid, stirring, makes it be uniformly dispersed, this is colloidal solution；(4) colloidal solution is added under stirring conditions
In main solution, 36h is stirred；(5) cysteine of 0.5g is dissolved with the deionized water of 5g, main solution is added；(6) with 5g go from
Main solution is added in 0.032g FD&C Huang and the red dissolution of 0.072g FD&C by sub- water；(7) be added 0.8g pomegranate essence, spend from
Sub- water is adjusted to final volume 400mL, is uniformly mixed to get premix matrix；(8) will dipping Topiramate-resin complexes with
The mixing of 0.25g polyoxyethylene sorbitan monoleate, is added in above-mentioned premix matrix, and deionized water is added and is adjusted to 500mL, is uniformly mixed, obtains
To suspension.
The preparation of [embodiment 9] carbinoxamine maleate oral sustained release suspension (dipping)
(1) 4g citric acid is dissolved in the deionized water of 200g, addition 60g sucrose, after stirring and dissolving, 150g wheat is added
Bud dextrin, stirring, makes it completely dissolved, this is main solution；(2) in another container, 50g glycerol is added and is heated to 49
DEG C, 0.9g methyl p-hydroxybenzoate and 0.1g propylparaben is then added, stirring makes it completely dissolved；(3) will
The solution of step (2) preparation is cooled to room temperature, and 2.0g xanthan gum is added slowly in solution to form uniform dispersion liquid,
Stirring, makes it be uniformly dispersed, this is colloidal solution；(4) colloidal solution is added in main solution under stirring conditions, is stirred
24h；(5) sodium pyrosulfite of 0.25g is dissolved with the deionized water of 5g, main solution is added；(6) use 5g deionized water will
0.004g lemon yellow and the dissolution of 0.004g famille rose, are added main solution；(7) 0.5g strawberry and flavoring banana essence is added, uses deionization
Water is adjusted to final volume 400mL, is uniformly mixed to get premix matrix；(8) carbinoxamine maleate-resin compounded will be impregnated
Object is mixed with 0.55g polyoxyethylene sorbitan monoleate, is added in above-mentioned premix matrix, and deionized water is added and is adjusted to 500mL, mixing is equal
It is even, obtain suspension.
The preparation of [embodiment 10, comparative example] carbinoxamine maleate oral sustained release suspension (coating)
(1) 4g citric acid is dissolved in the deionized water of 200g, addition 60g sucrose, after stirring and dissolving, 150g wheat is added
Bud dextrin, stirring, makes it completely dissolved, this is main solution；(2) in another container, 50g glycerol is added and is heated to 49
DEG C, 0.9g methyl p-hydroxybenzoate and 0.1g propylparaben is then added, stirring makes it completely dissolved；(3) will
The solution of step (2) preparation is cooled to room temperature, and 2.0g xanthan gum is added slowly in solution to form uniform dispersion liquid,
Stirring, makes it be uniformly dispersed, this is colloidal solution；(4) colloidal solution is added in main solution under stirring conditions, is stirred
24h；(5) sodium pyrosulfite of 0.25g is dissolved with the deionized water of 5g, main solution is added；(6) use 5g deionized water will
0.004g lemon yellow and the dissolution of 0.004g famille rose, are added main solution；(7) 0.5g strawberry and flavoring banana essence is added, uses deionization
Water is adjusted to final volume 400mL, is uniformly mixed to get premix matrix；(8) carbinoxamine maleate-resin of coating is multiple
It closes object to mix with 0.55g polyoxyethylene sorbitan monoleate, be added in above-mentioned premix matrix, deionized water is added and is adjusted to 500mL, mixing is equal
It is even, obtain suspension.
The In Vitro Dissolution of [embodiment 11, comparative experiments] dipping and coating carbinoxamine maleate oral sustained release suspension is bent
Line compares
In Vitro Dissolution test method is referring to the 2nd method (paddle method) of Chinese Pharmacopoeia, wherein dissolution medium is 0.4mol/L di(2-ethylhexyl)phosphate
Hydrogen potassium solution, the control of dissolution medium temperature are 37 ± 0.5 DEG C, revolving speed 50rpm, and dissolution medium volume is 900mL, in 0.5,1,2,
3, the dissolution medium that the temperature of same volume is 37 DEG C is replenished in time, with 0.45 μm of filter membrane mistake in 4,6,8, the separately sampled 5mL of 12h
Filter abandons primary filtrate about 3mL, takes subsequent filtrate about 2mL into sample injection bottle, detected, calculate the Accumulation dissolution of drug.Fig. 1 is
The dipping carbinoxamine maleate oral sustained release suspension and embodiment 10 of embodiment 9 are coated carbinoxamine maleate oral sustained release
Drug release rate of the suspension in dissolution medium 12h.
The dipping carbinoxamine maleate oral sustained release suspension and embodiment 10 of 1 embodiment 9 of table are coated maleic acid card ratio
Drug release rate of the husky bright oral sustained release suspension in 0.4mol/L potassium dihydrogen phosphate 12h
| Sample | 0.5h | 1h | 2h | 3h | 4h | 6h | 8h | 12h |
| Embodiment 9 | 6.2 | 13.3 | 28.8 | 40.0 | 54.0 | 77.2 | 87.4 | 93.6 |
| Embodiment 10 | 7.4 | 16.6 | 36.0 | 49.8 | 60.6 | 83.9 | 88.3 | 92.6 |
As shown in Figure 1, the maleic acid card of the carbinoxamine maleate of dipping-resin complexes suspension release and coating
It is more close than Sha Ming-resin complexes suspension release profiles, illustrate only reach by dipping and be coated identical slow
Release effect, it is even more important that maleic acid card ratio of the carbinoxamine maleate-resin complexes preparation of dipping than coating
Sha Ming-resin complexes prepare much simpler, and preparation process is easily controllable, drug high income.In addition, by tasting, it is real
It is more excellent to apply 9 mouthfeel of example, bitterness sense and feeling of grittiness are respectively less than contrast sample embodiment 10.
Claims (1)
1. a kind of preparation method of liquid slow-release preparation, the liquid slow-release preparation by drug-ion exchange resin complexes and
Suspension matrix is made, wherein the drug-ion exchange resin complexes are by drug, pharmaceutically acceptable ion exchange
Resin, polymer and plasticizer are made；
It is characterized in that, drug is carbinoxamine maleate, pharmaceutically acceptable ion exchange resin is AmberliteTM
IRP-69 resin, the preparation method include the following steps:
Step 1, the preparation of the carbinoxamine maleate drug-resin complex of dipping
(1) 640 g carbinoxamine maleates are dissolved in 8 L deionized waters；(2) it is slowly added to 2560 g under continuous mixing
Amberlite TMIRP-69 resin continuously stirs 6 h at 30 DEG C, stands, incline supernatant, and it is compound to obtain drug-resin
Object；(3) 8 L deionized waters are added into the drug-resin complex that (2) obtain, stir 5 min, wash away unbonded dissociate
Drug is stood, and incline supernatant；Step (3) are repeated to operate 3 times；(4) by (3) resulting drug-resin complex at 50 DEG C
Drying to water content is 5%；(5) 135 g 1,2-PDs are added in 22000 g Kollicoat SR 30D polymer, room
Temperature 1 h of stirring, obtains impregnating agent；(6) drug-resin complex obtained by step (4) is placed in wet granulator, 2370 g is soaked
Stain agent is added in drug-resin complex, stirs, shearing, to form homogeneous material；(7) by pharmaceutical-impregnated-obtained by step (6)
It is 5% that resin complexes, which are dried at 50 DEG C to water content, and repetition step (6) operation 2 times compound to get the drug-resin of dipping
Object；
Step 2, the preparation of suspension
(1) 4 g citric acids are dissolved in the deionized water of 200 g, 60 g sucrose of addition, after stirring and dissolving, 150 g wheats is added
Bud dextrin, stirring, makes it completely dissolved, this is main solution；(2) in another container, 50 g glycerol is added and are heated to 49
DEG C, 0.9 g methyl p-hydroxybenzoate and 0.1 g propylparaben is then added, stirs, makes it completely dissolved；(3)
Solution prepared by step (2) is cooled to room temperature, and 2.0 g xanthan gum are added slowly in solution to form uniform dispersion
Liquid, stirring, makes it be uniformly dispersed, this is colloidal solution；(4) colloidal solution is added in main solution under stirring conditions,
Stir 24 h；(5) sodium pyrosulfite of 0.25 g is dissolved with the deionized water of 5 g, main solution is added；(6) with 5 g deionizations
Water dissolves 0.004 g lemon yellow and 0.004 g famille rose, and main solution is added；(7) 0.5 g strawberry and flavoring banana essence is added, uses
Deionized water is adjusted to 400 mL of final volume, is uniformly mixed to get premix matrix；(8) carbinoxamine maleate-tree will be impregnated
Fat complexes are mixed with 0.55 g polyoxyethylene sorbitan monoleate, are added in above-mentioned premix matrix, and deionized water is added and is adjusted to 500 mL,
It is uniformly mixed, obtains suspension.
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| CN106109408A (en) * | 2016-07-01 | 2016-11-16 | 北京万全德众医药生物技术有限公司 | Topiramate slow release suspendible oral liquid and preparation method thereof |
| CN106727301A (en) * | 2016-12-25 | 2017-05-31 | 江苏先科药业有限公司 | A kind of sustained release mixed suspension preparation of breathing problem eliminating the phlegm and preparation method thereof |
| CN106727302A (en) * | 2016-12-25 | 2017-05-31 | 江苏先科药业有限公司 | A kind of sustained release preparation for kobadrin and preparation method thereof |
| CN108420791A (en) * | 2018-05-14 | 2018-08-21 | 山东达因海洋生物制药股份有限公司 | A kind of carbinoxamine maleate oral sustained release suspension and preparation method thereof |
| CN111603456A (en) * | 2020-07-08 | 2020-09-01 | 江苏四环生物制药有限公司 | Carbixamine maleate controlled-release dry suspension and preparation method thereof |
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| US4221778A (en) * | 1979-01-08 | 1980-09-09 | Pennwalt Corporation | Prolonged release pharmaceutical preparations |
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| CN101400343A (en) * | 2006-03-16 | 2009-04-01 | 特瑞斯制药股份有限公司 | Modified release formulations containing drug-ion exchange resin complexes |
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| CN1546008A (en) * | 2003-12-02 | 2004-11-17 | 沈阳药科大学 | Ambroxol hydrochloride liquid sustained release preparation and preparation method thereof |
| CN101400343A (en) * | 2006-03-16 | 2009-04-01 | 特瑞斯制药股份有限公司 | Modified release formulations containing drug-ion exchange resin complexes |
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