The compound slow release preparation of a kind of guaifenesin and pseudoephedrine
Technical field
The present invention relates to a kind of slow releasing preparation that is active component with guaifenesin, pseudoephedrine or its physiologically acceptable salt, belong to field of medicaments.
Background technology
Flu is the upper respiratory tract mucosa infection that is caused by a lot of dissimilar viruses, and its cardinal symptom often is nasal obstruction, sneeze, slight throat pain and heating etc., and systemic symptom has whole body discomfort, headache and myalgia etc.Because of no specific therapy can be sayed,, can only adopt symptomatic treatment to impel many remissions of flu so virus is firm then unnecessary.Because therefore the many symptoms that also do not have a kind of agents alleviate and deposit have various compound preparations to go on the market successively.These compound preparations select for use the medicine composition compound recipe of different curative effects to be used to alleviate simultaneous different symptoms.There is multiple symptom as patient,, then suits the medicine to the illness and use suitable compound preparation than more suitable with several individual event medicines, also more economical sometimes particularly at common cold initial stage.
Guaifenesin is an antitussive, is the guaiacol ether derivative, and there is zest oral back to gastric mucosa, can cause reflexive that the secretion of bronchus body of gland increases, and reduces sputum viscosity, belongs to the expectorant of feeling sick.Guaifenesin also has slight antitussive and sterilization antisepsis concurrently, can alleviate the foul smell of sputum.Heavy dose of fashion has the smooth muscle relaxation effect.The disease of main treatment is the respiratory tract infection of child's acute and chronic, and senile chronic bronchitis, emphysema, pulmonary tuberculosis etc.This product is evident in efficacy and expectorant that side effect is little, and the expectorant of this composition is the expectorant of sales volume first in Europe, the United States.
Pseudoephedrine claims d-pseudephedrine again, is the optical isomer of ephedrine, and the two is by extracting gained in Herba Ephedrae or the ephedra equisetina grass, but synthetic at present.Pseudoephedrine discharges norepinephrine by stimulating SNE, play sympatheticomimetic action indirectly, its preventing respiratory is identical with the effect and the ephedrine of nasal congestion, but boosting only is 1/5 of an ephedrine, strengthening heart rate and pressor effect only is 1/4 of ephedrine, aspect the expansion bronchus smooth muscle only be its 1/2.The pseudoephedrine vasoconstrictive has certain selectivity, mainly shrinks the upper respiratory tract blood vessel and makes and breathe unobstructedly, is used to shrink nasal mucosa vessels alleviating the nasal obstruction symptom, and is evident in efficacy and side effect is little, in the use usually with its hydrochlorate or sulfate.
Guaifenesin, pseudoephedrine are prepared into slow releasing preparation, can overcome the relevant symptom of flu, comprise simultaneously with symptoms such as cough, abundant expectoration, heat generation nasal obstruction, sneeze.Because guaifenesin, pseudoephedrine using dosage, rate of release, the difference of aspects such as absorbance need provide a kind of both releases, absorption to reach synchronous, so that better play synergistic compound preparation, reduce the medication number of times and make things convenient for patient's medication.
Summary of the invention
The purpose of this invention is to provide and a kind ofly can overcome the relevant symptom of flu, and all active component all are the compound preparation that slow release discharges.Technical solution of the present invention is as follows:
The slow releasing preparation that is active component with guaifenesin, pseudoephedrine or its physiologically acceptable salt of the present invention, comprise delivery system, described delivery system is made up of the label that drug slow is discharged and/or ball core and coating, part or all is present in described active component in label and/or the ball core, and the active component remainder is present in the coating.Described guaifenesin, pseudoephedrine or its physiologically acceptable salt all are slow release and discharge.Described " part ", can be one of in two kinds of active component or two, or one of in two kinds of active component or a part of two.This delivery system is made up of in guaifenesin, pseudoephedrine or its physiologically acceptable salt, slow-release material, filler, binding agent, coloring agent, lubricant, wetting agent, filmogen, porogen, the plasticizer one or more.
Of the present invention being characterised in that: guaifenesin, pseudoephedrine or its physiologically acceptable salt all are slow release and discharge.
Of the present invention being characterised in that: contain guaifenesin 100-1200mg in each dosage unit, pseudoephedrine or its physiologically acceptable salt 5-120mg.
Of the present invention being characterised in that: contain guaifenesin 200-800mg in each dosage unit, pseudoephedrine or its physiologically acceptable salt 30-120mg.
Of the present invention being characterised in that: the physiologically acceptable salt of described pseudoephedrine is pseudoephedrine hydrochlorate or pseudoephedrine sulfate.
Label of the present invention and/or ball core are by hydroxypropyl methylcellulose, the Sulisi aqueous dispersion, the water solublity coating powder, polyvinylpyrrolidone, ethyl cellulose, methylcellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, cellulose acetate, cellulose diacetate, Triafol T, hexadecanol, Rikemal B 200, stearic acid, glyceryl monostearate, Brazil wax, hydroxy methocel, polyvinyl alcohol, poly-phthalic acid vinyl acetate, polystyrene, carbopol, polrvinyl chloride, octadecanol, diethyl phthalate, dioctyl phthalate, Polyethylene Glycol, sodium alginate, chitosan, gelatin, Lac, pectin, guar gum, sucrose, lactose, starch, dextrin, Icing Sugar, low-substituted hydroxypropyl cellulose, cross linked polyvinyl pyrrolidone, cross-linking sodium carboxymethyl cellulose, mannitol, microcrystalline Cellulose, pregelatinized Starch, in the titanium dioxide one or more are made.
Filler of the present invention can be selected one or more in microcrystalline Cellulose, mannitol, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, poly-phthalic acid vinyl acetate, Polyethylene Glycol, chitosan, sucrose, lactose, starch, dextrin, Icing Sugar, cross linked polyvinyl pyrrolidone, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, the titanium dioxide for use.
In the optional water of binding agent of the present invention, ethanol, dehydrated alcohol, starch slurry, polyvidone, crospolyvinylpyrrolidone, hydroxypropyl methylcellulose and/or other cellulose families one or more.
Lubricant of the present invention can be selected one or more in magnesium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, polyethylene glycols, month pure magnesium sulfate of extension for use.
In the optional water of wetting agent of the present invention, ethanol, dehydrated alcohol, starch slurry, chloroform, acetone, polyvidone, crospolyvinylpyrrolidone, hydroxypropyl methylcellulose and/or other cellulose families one or more.
Coloring agent of the present invention can be selected ferrum oxide, amaranth, carmine, erythrosine, newly red, the lemon yellow of red, the red pigment of cowberry of red, beet red, lac, capsanthin, red rice, sunset yellow, indigo Huang, light blue for use, and for the various pigments that strengthen the acid pigment of above-mentioned water solublity dispersibility in oils and fats one or more.
Filmogen of the present invention can be selected one or more in ethyl cellulose, starch, Aquacoat, methylcellulose, cellulose acetate, acrylic resin, Opadry, the Sulisi for use.
Porogen of the present invention can be selected one or more in sucrose, mannitol, Polyethylene Glycol, polyvidone, copolyvidone, the dibutyl sebacate for use.
Plasticizer of the present invention is selected from one or more in Methyl Benzene-o-dicarboxylate, ethyl phthalate, diethyl phthalate, poly-phthalic acid vinyl acetate, polyvinyl alcohol, polystyrene, carbopol, polrvinyl chloride, dioctyl phthalate, triethyl citrate, Polyethylene Glycol, polyvidone, copolyvidone, the dibutyl sebacate.
Compound slow release preparation of the present invention is characterized in that: described preparation is tablet, granule, pill, capsule or suspensoid.
Compound slow release preparation of the present invention is characterized in that: the release characteristic of guaifenesin is: 1h:10%-45%, and 2h:30%-55%, 4h:45%-80% is more than the 8h:75%.
Compound slow release preparation of the present invention is characterized in that: the release characteristic of pseudoephedrine or its physiologically acceptable salt is: 1h:20-65%, and 2h:40-85%, 4h:60-90% is more than the 8h:75%.
Slow releasing preparation of the present invention, can not only overcome the relevant symptom of flu comprehensively, the performance synergistic interaction effect of compound drugs, and the release of two kinds of active component of slow releasing preparation of the present invention, absorb and to reach synchronously, it obtains desired drug release behavior in vivo and in vitro.Such drug release behavior can reduce takes number of times (by original-days 4 times, reduce to a day twice, promptly take night and morning).Therefore this preparation has the advantages that the medication number of times is few, medicine slowly discharges in vivo, blood drug level is steady, fluctuation is little, bioavailability is high, safe.
Specific embodiment
By following examples the slow releasing preparation that is active component with guaifenesin, pseudoephedrine or its physiologically acceptable salt of the present invention is done further to specify, but not as limitation of the present invention.
Embodiment 1
Prescription:
Guaifenesin |
800g |
Pseudoephedrine hydrochloride |
90g |
Hydroxypropyl methylcellulose E5 |
40g |
Brazil wax |
25g |
Microcrystalline Cellulose |
36g |
30 POVIDONE K 30 BP/USP
30Aqueous solution
|
In right amount |
Magnesium stearate |
In right amount |
The coating prescription:
Opadry |
15g |
Pure water |
Add to 100ml |
Preparation method:
(1) particulate preparation hydroxypropyl methylcellulose E5, microcrystalline Cellulose sieve respectively, with guaifenesin, pseudoephedrine hydrochloride and Brazil wax mix homogeneously, with 5% 30 POVIDONE K 30 BP/USP
30Aqueous solution is a binding agent system soft material, 20 mesh sieve system wet granulars, and 60 ℃ of dryings, 20 mesh sieve granulate, standby.
(2) preparation of coating solution adds to Opadry in the pure water, and adds pure water to 100ml, stirs 1 hour, and is standby.
(3) get (1) granule and carry out coating, obtain coated granule.
(4) in (3) gained granule, add an amount of magnesium stearate, mix homogeneously, tabletting promptly gets tablet.
(5) in (1) gained granule, add an amount of magnesium stearate, mix homogeneously, tabletting is got (2) coating solution, is wrapped in outside the tablet, gets final product coated tablet.
(6) get (3) gained particle packing in the hungry area softgel shell, promptly get capsule.
(7) get (3) gained granule direct packaging, promptly get granule.
The release characteristic of active component is as shown in table 1 in the gained different dosage form.
The release characteristic of active component in table 1 different dosage form
Embodiment 2
Prescription:
Guaifenesin |
400g |
Pseudoephedrine hydrochloride |
60g |
Hydroxypropyl methylcellulose K100 |
6g |
Hydroxypropyl methylcellulose E5 |
75g |
Microcrystalline Cellulose |
45g |
30 POVIDONE K 30 BP/USP
30Aqueous solution
|
In right amount |
Stearic acid |
In right amount |
The coating prescription:
Pseudoephedrine hydrochloride |
30g |
Opadry |
25g |
Water |
An amount of to dissolving fully |
Preparation method:
(1) particulate preparation hydroxypropyl methylcellulose, microcrystalline Cellulose, sieve mixes mixing, again with guaifenesin and pseudoephedrine hydrochloride mix homogeneously, with 8% 30 POVIDONE K 30 BP/USP respectively
30Aqueous solution is a binding agent system soft material, 20 mesh sieve system wet granulars, and 60 ℃ of dryings, 20 mesh sieve granulate, standby.
(2) to get pseudoephedrine hydrochloride soluble in water in the preparation of coating solution, adds Opadry, and mix homogeneously is standby.
(3) get (1) granule and carry out coating, obtain coated granule.
(4) in (3) gained granule, add an amount of stearic acid, mix homogeneously, tabletting promptly gets tablet.
(5) in (1) gained granule, add an amount of stearic acid, mix homogeneously, tabletting is got (2) coating solution, is wrapped in outside the tablet, gets final product coated tablet.
(6) get (3) gained particle packing in the hungry area softgel shell, promptly get capsule.
(7) get (3) gained granule direct packaging, promptly get granule.
The release characteristic of active component is as shown in table 2 in the gained different dosage form.
The release characteristic of active component in table 2 different dosage form
Embodiment 3
Prescription:
Guaifenesin |
600g |
Pseudoephedrine sulfate |
60g |
Pregelatinized Starch |
110g |
Carboxymethyl starch sodium |
20g |
Hydroxypropyl methylcellulose K4 |
7g |
Hydroxyethyl-cellulose |
72g |
Microcrystalline Cellulose |
60g |
Brazil wax |
50g |
30 POVIDONE K 30 BP/USP
30Aqueous solution
|
In right amount |
Pulvis Talci |
20g |
The coating prescription:
Opadry II |
30g |
Pure water |
1000ml |
Preparation method:
(1) each component is crossed 100 mesh sieves respectively in the prescription, and is standby;
(2) immediate-release granules preparation: with recipe quantity pregelatinized Starch, the abundant mixing of 1/2 amount carboxymethyl starch sodium, with the guaifenesin mix homogeneously, with 5% 30 POVIDONE K 30 BP/USP
30Aqueous solution is a binding agent system soft material, 20 mesh sieve system wet granulars, and 50 ℃ of forced air dryings, 20 mesh sieve granulate add 1/2 amount carboxymethyl starch sodium, magnesium stearate mixing, measure intermediate content, and it is heavy to calculate slice;
(3) slow-releasing granules preparation: with the mixed powder of recipe quantity hydroxypropyl methylcellulose K4 and pregelatinized Starch, microcrystalline Cellulose with the abundant mixing of equivalent incremental method, again with equivalent incremental method and guaifenesin mix homogeneously, with 5% 30 POVIDONE K 30 BP/USP
30Aqueous solution is a binding agent system soft material, 20 mesh sieve system wet granulars, and 50 ℃ of forced air dryings, 20 mesh sieve granulate add the magnesium stearate mixing, measure intermediate content, and it is heavy to calculate slice;
(4) with microcrystalline Cellulose, Brazil wax, cross 80 mesh sieves respectively, mix mixing, again with the pseudoephedrine sulfate mix homogeneously, with 7% 30 POVIDONE K 30 BP/USP
30Aqueous solution is a binding agent system soft material, 20 mesh sieve system wet granulars, and 60 ℃ of dryings, 20 mesh sieve granulate add the magnesium stearate mixing, measure intermediate content, and it is heavy to calculate slice;
(5) above-mentioned three kinds of granules are suppressed three-layer tablet with the 20*9mm drift.
(6) preparation of coating solution adds to Opadry II30g in the pure water, and adds pure water to 1000ml, stirs 1 hour.
(7) with the plain sheet of (5) gained, put to the coating machine, air blast is heated to about 50 ℃, at the uniform velocity sprays into the coating solution coating, and the limit sprays into the heating of coating solution snare drum wind, makes plain sheet temperature remain on 45-50 ℃, until evenly wrapping the thin film clothing, is drying to obtain.
The release characteristic of active component is as shown in table 3 in the resulting dosage forms.
Table 3
Embodiment 4
Prescription:
Guaifenesin |
600g |
Pseudoephedrine sulfate |
60g |
Celphere |
130g |
Hydroxypropyl methylcellulose E5 |
6g |
The Sulisi aqueous dispersion |
80g |
The water solublity coating powder |
5g |
Titanium dioxide |
5g |
Stearic acid |
5g |
30 POVIDONE K 30 BP/USP
30 |
In right amount |
Water |
In right amount |
Dehydrated alcohol |
In right amount |
The moon is hung pure magnesium sulfate |
In right amount |
The coating prescription:
Opadry |
30g |
Pure water |
Add to 1000ml |
Preparation method:
(1) sustained release micro-pellet of guaifenesin preparation
I, an amount of 30 POVIDONE K 30 BP/USP 30 is added an amount of dehydrated alcohol be made into 5% (w/w) solution, standby;
II, stearic acid is added an amount of dehydrated alcohol be mixed with 5% (w/w) solution, standby;
III, get an amount of recipe quantity celphere and put in the coating pan;
IV, take by weighing the stearic acid ethanol solution for preparing and be sprayed on the celphere;
V, spray 30 POVIDONE K 30 BP/USP 30 ethanol solutions successively, the hydrojet intermission also adds guaifenesin, treats that guaifenesin adheres to the ball wicking surface and repeats said process again, finishes until adding powder;
VI, taking-up made micropill dry 12 hours;
VII, sieve with 14 mesh sieves and 20 orders.
Promptly get guaifenesin pastille micropill, standby.
(2) pseudoephedrine sulfate slow-release micro-pill
I, preparation 10%HPMC E5 aqueous solution, standby;
II, get the Sulisi aqueous dispersion and add water, shake up standby;
III, preparation contain the water solublity coating solution of water solublity coating powder 10%, titanium dioxide 1%;
IV, preparation 40% pseudoephedrine sulfate aqueous solution add above-mentioned HPMC solution again, stir evenly standby;
V, get the celphere coating, spray step IV gained solution is collected micropill to finishing;
VI, to pseudoephedrine sulfate micropill coating, spray into the Sulisi aqueous dispersion after, wrap the water solublity coating solution again.
Promptly get pseudoephedrine sulfate pastille micropill, standby.
(3) preparation of coating solution: 30g adds in the pure water with Opadry, and adds pure water to 100ml, stirs 1 hour.
(4) get (1), (2) micropill carries out coating, obtains coated granule.
(5) in (4) gained granule, add an amount of month pure magnesium sulfate of extension, mix homogeneously, tabletting promptly gets tablet.
(6) in (1), (2) gained micropill, add an amount of month pure magnesium sulfate of extension, mix homogeneously, tabletting is got (3) coating solution, is wrapped in outside the tablet, gets final product coated tablet.
(7) get (1), (2) gained particle packing in the hungry area softgel shell, promptly get capsule.
(8) get (1), (2) gained granule direct packaging, promptly get granule.
The release characteristic of active component is as shown in table 4 in the gained different dosage form.
The release characteristic of active component in table 4 different dosage form