CN1241557C - Ambroxol guttate pill and method for preparing the same - Google Patents
Ambroxol guttate pill and method for preparing the same Download PDFInfo
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- CN1241557C CN1241557C CN 200310115271 CN200310115271A CN1241557C CN 1241557 C CN1241557 C CN 1241557C CN 200310115271 CN200310115271 CN 200310115271 CN 200310115271 A CN200310115271 A CN 200310115271A CN 1241557 C CN1241557 C CN 1241557C
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- ambroxol
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- 239000006187 pill Substances 0.000 title claims abstract description 52
- 229960005174 ambroxol Drugs 0.000 title claims abstract description 39
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 29
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 20
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 20
- 239000000463 material Substances 0.000 claims abstract description 15
- 206010006451 bronchitis Diseases 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 208000006673 asthma Diseases 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract 2
- 229960000985 ambroxol hydrochloride Drugs 0.000 claims description 37
- QNVKOSLOVOTXKF-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]cyclohexan-1-ol;hydron;chloride Chemical compound Cl.NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 QNVKOSLOVOTXKF-UHFFFAOYSA-N 0.000 claims description 36
- 239000000758 substrate Substances 0.000 claims description 32
- -1 Lac Polymers 0.000 claims description 13
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 229920002545 silicone oil Polymers 0.000 claims description 10
- 238000009833 condensation Methods 0.000 claims description 9
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- 230000004927 fusion Effects 0.000 claims description 8
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- 229920002472 Starch Polymers 0.000 claims description 6
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 6
- 229920000159 gelatin Polymers 0.000 claims description 6
- 235000019322 gelatine Nutrition 0.000 claims description 6
- 235000011187 glycerol Nutrition 0.000 claims description 6
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 6
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
- 229920000570 polyether Polymers 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 239000008117 stearic acid Substances 0.000 claims description 6
- 235000021355 Stearic acid Nutrition 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 4
- 229940057995 liquid paraffin Drugs 0.000 claims description 4
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 4
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- 238000005516 engineering process Methods 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 15
- 229960001361 ipratropium bromide Drugs 0.000 description 9
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 description 9
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 6
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- 238000013401 experimental design Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 206010036790 Productive cough Diseases 0.000 description 4
- 239000003172 expectorant agent Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 206010002198 Anaphylactic reaction Diseases 0.000 description 3
- 241001269238 Data Species 0.000 description 3
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- 238000006243 chemical reaction Methods 0.000 description 3
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- 239000007788 liquid Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 206010006458 Bronchitis chronic Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010062717 Increased upper airway secretion Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 208000037883 airway inflammation Diseases 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000003064 anti-oxidating effect Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 208000007451 chronic bronchitis Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000428 dust Substances 0.000 description 2
- 230000003419 expectorant effect Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229940093181 glucose injection Drugs 0.000 description 2
- 235000015250 liver sausages Nutrition 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 229940066491 mucolytics Drugs 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 229940100688 oral solution Drugs 0.000 description 2
- 208000026435 phlegm Diseases 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000000884 Airway Obstruction Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- 208000005107 Premature Birth Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 208000018569 Respiratory Tract disease Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000009798 acute exacerbation Effects 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OJGDCBLYJGHCIH-UHFFFAOYSA-N bromhexine Chemical class C1CCCCC1N(C)CC1=CC(Br)=CC(Br)=C1N OJGDCBLYJGHCIH-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 210000004081 cilia Anatomy 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000011443 conventional therapy Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
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- 230000007613 environmental effect Effects 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 239000002389 essential drug Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
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- 230000005764 inhibitory process Effects 0.000 description 1
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- 210000004185 liver Anatomy 0.000 description 1
- 239000003580 lung surfactant Substances 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention relates to a therapeutic medicine for bronchitis, asthma and pulmonary diseases and a preparation method thereof. The present invention has the purpose on making up the shortages of the prior art, and provides the dripping pill of ambroxol with the advantages of high biologic use degree, quick medicine release, quick effects, small side effects and convenient carrying and the preparation method thereof for wide patients and medical workers. The present invention has the raw materials of ambroxol (comprises the salt of the ambroxol), and base materials such as the polyethylene glycol of a surface acting agent, etc. are added in the ambroxol according to a certain ratio; the mixed materials are heated to be melting, and are stirred uniformly; the mixed materials are put in a special pill dropping machine, and a condensing agent is dropped in the mixed materials according to a proper speed; the dripping pills of ambroxol are obtained after the mixed materials are cooled.
Description
[technical field] the present invention relates to a kind of medicine for the treatment of bronchitis, asthma and pneumonopathy class disease and preparation method thereof.
[background technology] ambroxol is a bromhexine metabolite in vivo, has the phlegm dissolving effect, thereby can make the how sticking fibrous fracture dilution sputum of apoplexy due to phlegm, and reduces expectorant viscosity by suppressing the synthetic of glycoprotein, makes expectorant be convenient to discharge.Be applicable to the thick sputum that acute and chronic respiratory tract disease (as acute and chronic bronchitis, bronchial asthma, bronchiectasis, pulmonary tuberculosis etc.) causes, dys-expectoration etc.
One. pharmacology and drug effect
Chronic obstructive pulmonary disease (COPD) is the respiratory system commonly encountered diseases, is principal character with the airway obstruction that can not reverse fully, and Chang Fanfu morbidity and carrying out property increase the weight of.At present still do not have special Therapeutic Method and can contain its development.The main pathological characters of COPD is exactly the flow limitation due to the airway inflammation.Airway inflammation causes the swelling of air flue mucosa, oozes out and increases, and influences patient's ventilatory function.
Ambroxol hydrochloride is a kind of efficient mucolytic agent, also has antiinflammatory, antioxidation and the synthetic effect of promotion alveolar surfactant simultaneously.Tan Lijie etc. discover that ambroxol hydrochloride has protective effect to the decline of PS due to the thoracic surgery.Zhang Lei etc. then find to add immediately puerperal effectively prevention of preterm birth youngster respiratory distress syndrome of usefulness ambroxol hydrochloride (intravenously administrable).Ipratropium bromide can reduce airway secretions by its anticholinergic effect, has the effect of expansion bronchus simultaneously concurrently.The essential drugs of COPD treatment has been classified it as in whole world COPD proposal (GOLD).
Two. clinical effectiveness
A clinical example is as follows:
COPD inpatient 47 examples are divided into two groups at random, and except that conventional therapy, first group (25 example) assisted and added ipratropium bromide 0.5mg+ normal saline 3ml atomizing suction; Second group (22 example) auxilliary to be added ambroxol hydrochloride 15mg+ ipratropium bromide 0.5mg+ normal saline 1ml atomizing and sucks, and measures FEV1 before the treatment and behind the treatment 3d.The result: the effect that second group of treatment promotes FEV1 significantly is better than first group (P＜0.05), and makes and significantly shorten (P＜0.05) average time in hospital day.
The research of this group discloses, though single ipratropium bromide atomizing sucks and can promote FEV1, but the effect that ambroxol hydrochloride and ipratropium bromide combined atomizing suck significantly is better than single ipratropium bromide atomizing and sucks (P＜0.05), and the average time in hospital day (P＜0.05) of COPD inpatient can be significantly shortened in the two coupling, makes COPD acute exacerbation phase patient's remission time shorten [1].
Research article according to another Han Juyun discloses: ambroxol hydrochloride and ipratropium bromide share, effect obviously is better than the latter and uses separately: ambroxol hydrochloride is a kind of newer mucolytic agent, main effect is that the transportation of activation cilium promotes mucus to get rid of, and significantly promotes expectoration, improves breath state.Ambroxol hydrochloride also has antioxidation, inhibition inflammatory mediator, lax airway smooth muscle, promotes the anabolic effect of lung surface mass, can improve the concentration of antibiotic in lung tissue simultaneously again.In this research, it is 75.56% that A organizes independent medication effective percentage, and B organizes two medicines and share the obvious synergistic effect, and total effective rate reaches 90.24%, compares significant difference (P＜005) with the A group of independent medication.Suck treatment, directly absorb by mucosa, medicine directly acts on target organ, and drug dose little [2].
Three. the problem of existence
The ambroxol preparation that utilizes prior art to obtain has ambroxol hydrochloride injection, ambroxol hydrochloride glucose injection, ambroxol hydrochloride sheet, ambroxol hydrochloride capsule (slow release), ambroxol hydrochloride oral solution etc.
Owing to reasons such as technologies of preparing, exist that dissolve scattered time limit is long, dissolution is low, absorption is relatively poor after most of oral formulations are taken, problem such as liver sausage first pass effect and bioavailability are lower, thereby influence the performance of drug effect, also directly affect the effect of treatment.
And injection often is easy to generate anaphylaxis or untoward reaction etc., and it is big yet to exist operation easier simultaneously, and the patient suffering is also big, makes and medical treatment cost high the shortcoming that patient economy burden is heavy.Therefore, be necessary to seek better Ambroxol dosage form to satisfy the needs that clinical treatment and family use.
[summary of the invention] purpose of the present invention is to remedy the deficiencies in the prior art, provides a kind of bioavailability height to extensive patients and medical personnel, release fast, quick produce effects, toxic and side effects is littler, and uses ambroxol dripping pill easy to carry and preparation method thereof.
[technical scheme] is primary raw material with ambroxol (comprising its esters), according to certain ratio, adds substrate such as surfactant polyethylene, is prepared from through specific technology, apparatus processing again.In the practicality often so that its esters chemical compound---ambroxol hydrochloride is as raw material.Can adopt following technical process to obtain ambroxol dripping pill involved in the present invention:
One. prescription
Ambroxol (comprise its esters, as: ambroxol hydrochloride)---have another name called ammonia bromohydrin, bromine hexamethylene ammonia alcohol, long-acting acetylcystein, mucosolvan, English name Ambroxol, Chinese phonetic alphabet Anxiusuo;
Ambroxol hydrochloride English name Ambroxol Hydrochloride, Chinese phonetic alphabet Yansuan Anxiusuo;
Substrate---substrate can be selected Polyethylene Glycol for use
1500～20000, in the material such as stearic acid, sodium stearate, glycerin gelatine, glyceryl monostearate, Lac, polyoxyethylene monostearate, polyethers, carboxymethyl starch sodium any one or a few mix mutually;
Ambroxol (comprising its esters) counts 1 by weight with the ratio of substrate: (0.5～6).
Two. preparation technology
The first step is mixed ambroxol (comprising its esters) with substrate, substrate can be selected Polyethylene Glycol for use
1500～20000, any one or several mixing wherein in the materials such as stearic acid, sodium stearate, glycerin gelatine, glyceryl monostearate, Lac, polyoxyethylene monostearate, polyethers, carboxymethyl starch sodium use;
Second step placed above mixture heats in the heating container while stirring until fusion;
The 3rd step was adopted special-purpose drop pill machine (as the DW-35 type drop pill machine of Taixing, Jiangsu second pharmaceutical machine factory production), and the temperature control system of adjustment drop pill machine, make the water dropper temperature of drop pill machine remain on (60～100) ℃, and the thermograde that makes condensing agent in the condensation column is (40～10) ℃ for (40～10) ℃ → (5～-15) ℃-be condensation column upper temp, and bottom temp is (5～-15) ℃;
The 4th step treated that the temperature of condensing agent in dropping-pill machine head and the condensation column is stable respectively and was in for the 3rd step during desired state of temperature, and fused material is splashed in the condensing agent with suitable speed by the water dropper of drop pill machine.Condensing agent can be any one in liquid paraffin, methyl-silicone oil, the vegetable oil;
The drop pill that the 5th step will be shunk molding by the outlet of drop pill machine takes out, and removes the condensing agent on surface, is drying to obtain.
The ambroxol preparation that [beneficial effect] utilizes prior art to obtain has ambroxol hydrochloride injection, ambroxol hydrochloride glucose injection, ambroxol hydrochloride sheet, ambroxol hydrochloride capsule (slow release), ambroxol hydrochloride oral solution etc.
Owing to reasons such as technologies of preparing, exist that dissolve scattered time limit is long, dissolution is low, absorption is relatively poor after most of oral formulations are taken, problem such as liver sausage first pass effect and bioavailability are lower, thereby influence the performance of drug effect, also directly affect the effect of treatment.
And injection often is easy to generate anaphylaxis or untoward reaction etc., and it is big yet to exist operation easier simultaneously, and the patient suffering is also big, makes and medical treatment cost high the shortcoming that patient economy burden is heavy.
Ambroxol dripping pill involved in the present invention is compared with present existing dosage form, has following beneficial effect:
1. ambroxol dripping pill involved in the present invention; utilize surfactant polyethylene etc. to be substrate; make solid dispersion with Ambroxol (comprising its esters); making medicine be molecule, colloid or microcrystalline state is scattered in the substrate; the total surface area of medicine increases, and substrate is hydrophilic, and medicine is had wetting action; can make that medicine is rapidly molten to loose into microgranule or solution, thereby make the dissolving of medicine and absorb and accelerate.Thereby improved bioavailability, brought into play efficient, quick-acting effects etc.
Compare with the administering mode of traditional oral formulations, exist essential distinction.Drop pill with the solid dispersion technology preparation can adopt oral and sublingual administration, and effective ingredient is fully contacted with mucomembranous surface, absorbs by mucomembranous epithelial cell, directly enters blood circulation.Especially sublingual administration administration can directly enter blood circulation without gastrointestinal tract and liver, has avoided first pass effect effectively, has also avoided gastrointestinal irritation, thereby it is rapid to have an onset, bioavailability height, characteristics such as side effect is little, and medication is convenient.
Compare with injection, avoided medicine and solvent thereof and adjuvant directly to enter sanguimotor process, can reduce acute toxic and side effects effectively and take place, safe in utilization, effect is lasting, applied range; Injection also is easy to generate anaphylaxis or untoward reaction etc. simultaneously, and it is big yet to exist operation easier simultaneously, and the patient suffering is also big, makes and medical treatment cost high the shortcoming that patient economy burden is heavy.
2. ambroxol dripping pill involved in the present invention, volume is little, and is in light weight, is applicable to and carries.After containing entrance cavity, contact promptly with saliva and to dissolve rapidly, and absorb by oral mucosa, not only rapid-action, and the influence of not taken food, promptly all can containing take after meal ante cibum.
3. the contained drug dose of each drop pill of this preparation is accurate, and the patient who is suitable for various disease, the different state of an illness, all ages and classes more flexibly and accurately grasps dosage.
4. production technology, the equipment of preparation drop pill are simple, easy to operate, the automaticity height, and labor intensity is low, the production efficiency height.Workshop does not have dust simultaneously, helps labor protection and environmental protection yet.
The preparation drop pill need adopt high-tech means and equipment, and principal agent is uniformly dispersed in substrate, and dosage is accurate, and the ball method of double differences is different little than tablet; Production cost is lower than with below 50% of kind tablet.
5. this preparation is by after the heating of solid drugs and substrate, being melt into liquid state, splashes into to make in the not miscible condensed fluid.Therefore, the stability of drug height, not facile hydrolysis, oxidation, and the operation be under liquid state, to carry out, no dust pollution is not subject to the influence of crystal formation, thereby has guaranteed the quality of medicine, has increased stability.
In sum, make this preparation have the advantage of triple effect (quick-acting, efficient, long-acting), three little (taking dose is little, toxicity is little, side effect little), five convenience (convenient for production, store convenience, convenient transportation, easy to carry, easy to use).
The ambroxol dripping pill that [specific embodiment] is involved in the present invention, a concrete example of implementing is as follows:
One. prescription
Ambroxol raw material in this example, the ambroxol hydrochloride that adopts Han River Pharmaceutical limited company to produce, October 27 2003 date of manufacture, lot number 0310015, total impurities＜0.07%, content 100.2%;
The ratio of ambroxol hydrochloride and substrate is 1: 2;
This example mesostroma is selected Polyethylene Glycol for use
4000, commercially available common product all can.
Two. preparation technology
The first step is with ambroxol hydrochloride and Polyethylene Glycol
4000According to the weight portion meter, evenly standby with 1: 2 mixed;
Second step placed above mixture in the heating container, heated while stirring until fusion;
The 3rd step was adopted homemade drop pill machine, adjust the temperature control system of drop pill machine, make the water dropper temperature of drop pill machine remain on (80～85) ℃ (error＜2%), and to make in the condensation column thermograde of condensing agent be 20 ℃ → 0 ℃ (be that the condensation column upper temp is 20 ℃, bottom temp is 0 ℃, error＜5%);
The 4th step temperature for the treatment of dropping-pill machine head and condensation column inner condensat liquid has been stable respectively to be in for the 3rd step during desired state of temperature, with the water dropper of fused material, splash into methyl-silicone oil (this example condensing agent is selected methyl-silicone oil for use) with suitable speed by the drop pill machine;
The drop pill that the 5th step will be shunk molding by the outlet of drop pill machine takes out, and removes the condensed fluid on surface, is drying to obtain.
Three. result of the test
Example one selects different substrates to carry out the experiment of prescription
Experimental design: carry out the influence of prescription in order to observe ambroxol hydrochloride and different substrates, respectively with Polyethylene Glycol to product involved in the present invention
4000Stearic acid, sodium stearate, glycerin gelatine, glyceryl monostearate, Lac, the polyoxyethylene monostearate, polyethers, carboxymethyl starch sodium is a substrate, substrate with different is even with 1: 2 mixed respectively with ambroxol hydrochloride, other is all according to the step of stipulating in [specific embodiment], adopt electrically heated mode that each group prepared materials is heated to fusion respectively, utilize homemade drop pill machine, regulate the requirement that its temperature control system makes the 3rd step of preparation technology in satisfied [specific embodiment], with the methyl-silicone oil is condensing agent, the technical process given according to [specific embodiment] is prepared, can obtain the prescription experiment of 9 [] and different substrates, and obtain 9 groups of different experimental results and see attached list one.
The experiment of example two hydrochloric acid ambroxols and the different proportionings of substrate
Experimental design: carry out the influence of prescription in order to observe ambroxol hydrochloride and different substrates to product involved in the present invention, respectively with 1: 0.5/1: 1/1: 2/1: 3/1: 4/1: 5/1: 6 ratio, with ambroxol hydrochloride and Polyethylene Glycol
4000Mix homogeneously, other is according to defined terms and step in [specific embodiment], adopt electrically heated mode that each group prepared materials is heated to fusion respectively, utilize homemade drop pill machine, regulate the requirement that its temperature control system makes the 3rd step of preparation technology in satisfied [specific embodiment], with the methyl-silicone oil is condensing agent, the technical process given according to [specific embodiment] is prepared, can obtain 7 ambroxol hydrochlorides and substrate and carry out the prescription experiment of different proportion, and obtain 7 groups of different experimental results and see attached list two.
Select the experiment of different water dropper temperature in example three preparation process
Experimental design: in order to observe of the influence of the different water dropper temperature of selection in the preparation process to product involved in the present invention, utilize homemade drop pill machine, regulate its temperature control system, make the water dropper temperature remain on 60 ℃ respectively, 70 ℃, 80 ℃, 90 ℃, 100 ℃, temperature error＜2%, and making condensate temperature satisfy the requirement in the 3rd step of preparation technology in [specific embodiment], all according to defined terms and step in [specific embodiment], substrate is selected Polyethylene Glycol for use for other
4000, ambroxol hydrochloride and Polyethylene Glycol
4000Mixed with 1: 2 is even, adopt electrically heated mode that the material that configures is heated to fusion, with the methyl-silicone oil is condensing agent, be prepared respectively according to the given technology in front [specific embodiment], can obtain 5 experiments under the condition of different temperatures, and obtain 5 groups of different experimental datas and see attached list three.
Select the experiment of different condensing agents in example four preparation process
Experimental design: select of the influence of different condensing agents in the preparation process to product involved in the present invention in order to observe, respectively with liquid paraffin, methyl-silicone oil, vegetable oil as condensing agent, all according to defined terms and step in [optimum implementation], substrate is selected Polyethylene Glycol for use for other
4000, ambroxol hydrochloride and Polyethylene Glycol
4000Mixed with 1: 2 is even, adopt electrically heated mode that the material that configures is heated to fusion, utilize homemade drop pill machine, regulate the requirement that its temperature control system makes the 3rd step of preparation technology in satisfied [specific embodiment], be prepared respectively according to the given technology in front [specific embodiment] again, can obtain 3 different experiments, and obtain 3 groups of different experimental datas and see attached list four.
Select the experiment of different condensing agent temperature in example five preparation process
Experimental design: select of the influence of different condensing agent temperature in the preparation process to product involved in the present invention in order to observe, regulate the refrigeration control system of drop pill machine, make the thermograde of condensing agent in the condensation column remain on 20 ℃ →-5 ℃ respectively, 30 ℃ →-10 ℃, 40 ℃ →-15 ℃, temperature error＜5%, all according to defined terms and step in [optimum implementation], substrate is selected Polyethylene Glycol for use for other
4000, ambroxol hydrochloride and Polyethylene Glycol
4000Mixed with 1: 4 is even, adopt electrically heated mode that the material that configures is heated to fusion, utilize homemade drop pill machine, regulating its temperature control system makes the temperature of dropping-pill machine head satisfy the requirement in the 3rd step of preparation technology in [specific embodiment], with the methyl-silicone oil is condensing agent, be prepared respectively according to the given technology in front [specific embodiment] again, can obtain 3 different experiments, and obtain 3 groups of different experimental datas and see attached list five.
Table one ambroxol hydrochloride and the mutually blended experiment of different substrates
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 4000 | 33.3 | 93 | ＜30 | ＜10 | +++ |
| Stearic acid | 33.3 | 86 | ＞30 | ＜10 | ++ |
| Sodium stearate | 33.3 | 89 | ＞30 | ＜10 | +++ |
| Glycerin gelatine | 33.3 | 52 | ＞30 | ＞10 | + |
| Glyceryl monostearate | 33.3 | 75 | ＜30 | ＜10 | + |
| Lac | 33.3 | 32 | ＞30 | ＞10 | - |
| The polyoxyethylene monostearate | 33.3 | 83 | ＜30 | ＜10 | ++ |
| Polyethers | 33.3 | 82 | ＜30 | ＜10 | ++ |
| Carboxymethyl starch sodium | 33.3 | 80 | ＜30 | ＜10 | ++ |
Result by table one can see: in an embodiment, when selecting different substrate, quality index such as, hardness different to rounding rate, the ball method of double differences, dissolve scattered time limit all have influence in various degree.
Table two hydrochloric acid ambroxol and Polyethylene Glycol
4000The experiment of different proportionings
| Ambroxol hydrochloride: Polyethylene Glycol 4000 | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| 1∶0.5 | 66.7 | 52 | ＜30 | ＞10 | + |
| 1∶1 | 50.0 | 74 | ＜30 | ＜10 | ++ |
| 1∶2 | 33.3 | 95 | ＜30 | ＜10 | +++ |
| 1∶3 | 25.0 | 96 | ＜30 | ＜10 | +++ |
| 1∶4 | 20.0 | 93 | ＜30 | ＜10 | +++ |
| 1∶5 | 16.7 | 96 | ＜30 | ＜10 | +++ |
| 1∶6 | 14.3 | 96 | ＜30 | ＜10 | +++ |
Result by table two can see: in an embodiment, and when ambroxol hydrochloride and Polyethylene Glycol
4000Mixed proportion＞1: 1 o'clock, every index all enters a preferable scope.
Table three is selected the experiment of different water dropper temperature
| The water dropper temperature | Effective ingredient (%) | The rounding rate | Dissolve scattered time limit | The ball method of double differences is different | Hardness |
| 60℃ | 33.3 | 62 | ＜30 | ＞10 | + |
| 70℃ | 33.3 | 90 | ＜30 | ＜10 | ++ |
| 80℃ | 33.3 | 93 | ＜30 | ＜10 | +++ |
| 90℃ | 33.3 | 80 | ＜30 | ＜10 | +++ |
| 100℃ | 33.3 | 73 | ＜30 | ＞10 | + |
Result by table three can see: in an embodiment, when selecting different water dropper temperature, to the rounding rate, the ball method of double differences is different and the hardness number influence is bigger, and dissolve scattered time limit is not had obvious influence.
Table four is selected the experiment of different condensing agents
| Condensing agent | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Liquid paraffin | 33.3 | 75 | ＜30 | ＜10 | ++ |
| Methyl-silicone oil | 33.3 | 96 | ＜30 | ＜10 | +++ |
| Vegetable oil | 33.3 | 86 | ＜30 | ＞10 | + |
Result by table four can see: bigger to rounding rate and hardness number influence when selecting different condensing agents in an embodiment, and to the ball method of double differences is different certain influence is arranged, and dissolve scattered time limit is not had obvious influence.
Table five is selected the experiment of different condensing agent temperature
| The condensing agent temperature | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| 20℃→-5℃ | 33.3 | 94 | ＜30 | ＜10 | +++ |
| 30℃→-10℃ | 33.3 | 93 | ＜30 | ＜10 | +++ |
| 40℃→-15℃ | 33.3 | 81 | ＜30 | ＞10 | +++ |
Result by table five can see: in an embodiment, when selecting different condensing agent temperature, rounding rate index is had certain influence, and to dissolve scattered time limit, the ball method of double differences is different and index influence such as hardness is less.
(annotate: the hardness method for expressing in the subordinate list, adopt drop pill is placed on the glass plate, press...with one's finger it, observe its metamorphosis."+" expression flicking promptly is out of shape, " ++ " expression distortion of firmly pressing, and " +++" expression is indeformable by it.)
The partial reference data is as follows:
1. Xie Hanhua, Huang Qian, Gu Xueren. ambroxol hydrochloride and ipratropium bromide atomization inspiration treatment are to the influence of the patients with chronic obstructive pulmonary diseases pulmonary function and the course of disease. and contemporary Chinese medical journal 2002,10-12 (19) is P.46-47
2. Han Ju cloud. the atomizing of ipratropium bromide associating ambroxol sucks the effect in the chronic bronchitis treatment. and Chinese basic unit medicine 2003,10-10 (10) is P.994-995.
Claims (7)
1. an ambroxol dripping pill that is used for the treatment of bronchitis, asthma and pneumonopathy class disease is a raw material with ambroxol or its esters, is prepared from the pharmaceutically suitable carrier as substrate.Wherein:
1.1 substrate: Polyethylene Glycol
1500～20000, stearic acid, sodium stearate, glycerin gelatine, glyceryl monostearate, Lac, polyoxyethylene monostearate, polyethers, carboxymethyl starch sodium, the mixture of one or more in the above-mentioned adjuvant;
1.2 the ratio of ambroxol or its esters and substrate is counted 1: 0.5～1: 6 by weight.
2. ambroxol dripping pill as claimed in claim 1 is characterized in that: the salt of described ambroxol is an ambroxol hydrochloride.
3. ambroxol dripping pill as claimed in claim 1 is characterized in that: the proportioning of described ambroxol or its esters and described substrate is 1: 1～1: 4.
4. ambroxol dripping pill as claimed in claim 1 is characterized in that: described substrate is Polyethylene Glycol
4000～10000
5. preparation method that is used for the described ambroxol dripping pill of claim 1 is characterized in that being made of following steps:
5.1 ambroxol or its esters are mixed with substrate, and described substrate is Polyethylene Glycol
1500～20000, stearic acid, sodium stearate, glycerin gelatine, glyceryl monostearate, Lac, polyoxyethylene monostearate, polyethers, carboxymethyl starch sodium, the mixture of one or more in the above-mentioned adjuvant;
5.2 above mixture placed heat while stirring in the heating container until fusion, standby;
5.3 adjust the temperature control system of drop pill machine, make the water dropper temperature of drop pill machine remain on 60 ℃～100 ℃, and to make the thermograde of condensing agent in the condensation column be 40 ℃～10 ℃ → 5 ℃～-15 ℃;
5.4 when treating that the temperature of condensing agent in dropping-pill machine head and the condensation column is stable respectively and reaching desired temperature, the water dropper by the drop pill machine of fused material is splashed in the condensing agent;
Take out 5.5 will shrink the drop pill of molding by the outlet of drop pill machine, remove the condensing agent on surface, be drying to obtain.
6. as the preparation method of ambroxol dripping pill as described in the claim 5, it is characterized in that: described condensing agent is any one in liquid paraffin, methyl-silicone oil, the vegetable oil.
7. as the preparation method of ambroxol dripping pill as described in the claim 5, it is characterized in that: the temperature range of dripping dropping-pill machine head in the system process is 70 ℃～90 ℃.
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