CN103705493B - Dextromethorphan hydrobromide oral dispersible film agent and preparation method thereof - Google Patents
Dextromethorphan hydrobromide oral dispersible film agent and preparation method thereof Download PDFInfo
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- CN103705493B CN103705493B CN201310722331.1A CN201310722331A CN103705493B CN 103705493 B CN103705493 B CN 103705493B CN 201310722331 A CN201310722331 A CN 201310722331A CN 103705493 B CN103705493 B CN 103705493B
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Abstract
The invention provides a dextromethorphan hydrobromide oral dispersible film agent. The film agent comprises dextromethorphan hydrobromide, polacrilin or polacrilin potassium with grain diameter of 50-150mu m, a film forming agent, a plasticizer, a disintegrating agent, a wetting agent and water, wherein dextromethorphan hydrobromide and polacrilin or polacrilin potassium form a dextromethorphan hydrobromide compound, and the weight ratio of dextromethorphan hydrobromide to polacrilin or polacrilin potassium is 1:1-1:2, and preferably 1:1.3-1:1.5; the film forming agent comprises hydroxypropyl methylcellulose E3 and hydroxypropyl methylcellulose E50. The invention also provides a preparation method of the dextromethorphan hydrobromide oral dispersible film agent. The dextromethorphan hydrobromide oral dispersible film agent can well solve the problem of poor taste of dextromethorphan hydrobromide, is particularly suitable for children and old patients, and can remarkably improve the compliance of patients. An oral film tablet is nicer by an optimal preparation method.
Description
Technical field
The invention belongs to pharmaceutics field, be specifically related to a kind of dextromethorphan hydrobromide oral cavity and disperse membrane and preparation method thereof.
Background technology
Dextromethorphan hydrobromide, claims again dextro-methorphan, is central antitussive, and antitussive effect intensity equates with codeine or is slightly strong, nothing analgesia and syngignoscism, and long-term taking has no drug resistance and addiction, is applicable to the cough causing because of flu, asthma and pulmonary tuberculosis etc.Clinical practice shows that it is safe, and untoward reaction is few.The Suppress of market sale is mainly injection and various deglutition type oral formulations, as syrup, soft capsule, oral liquid, tablet, granule, chewable tablet, capsule, slow releasing tablet, dispersible tablet, drop pill, oral administration solution.But old people, child and some dysphagia patient, for the poor compliance of above-mentioned preparation.Therefore, be necessary to develop one and take more convenient, the better preparation of patient's compliance.
Oral cavity dispersion membrane (tongue membrane) is a kind of emerging pharmaceutical preparation, is a kind of brand-new drug-supplying system.Medicine carrying dosage form is a frivolous membrane, is directly placed on tongue, and release is rapid, and taste is pleasant, and profile is lovely, is especially deeply subject to liking of child patient.At present, just at product---the Thin Strips of the Novartis of America & Canada market fast sale, be exactly the oral cavity dispersion membrane dosage form for child's marketing specially, release again the similar membrane agent kind for baby market.
Contrast existing pharmaceutical dosage form, along with expanding economy and the transformation of Working and life styles now, a kind of brand-new anhydrous drug-supplying system of the market demand, solves the compliance of children's and children, privacy, the convenience of old people's medication and the feasibility of especial patient medication of white-collar job gang medication.
Chinese patent application (publication number CN102641258A) discloses a kind of spongiform dextromethorphan hydrobromide membrane with micropore, comprises dextromethorphan hydrobromide, water-soluble high-molecular material and is dispersed in the water-insoluble micropowder in described water-soluble high-molecular material.Wherein water-soluble high-molecular material is made up of lower molecular weight water-soluble high-molecular material and higher molecular weight water-soluble high-molecular material.It successfully, in ensureing the physical strength and toughness of film, reaches again the object of rapid release.
But dextromethorphan hydrobromide taste is extremely bitter, and has numb feeling in the tongue, and common correctives cannot be covered its bad mouthfeel; And adjuvant viscosity is large, disperse inhomogeneously, in film coating, easily cause " scratch ", affect the outward appearance of diaphragm and being uniformly distributed of active component, cause clinical administration dosage inaccurate.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, provide a kind of dextromethorphan hydrobromide oral cavity to disperse membrane and preparation method thereof.Described dextromethorphan hydrobromide oral cavity disperses membrane to solve well the bad sensory issues of dextromethorphan hydrobromide hardship, fiber crops, and by preferred preparation method, makes membrane surface smooth, smooth.
In order to realize foregoing invention object, the present invention has adopted following technical scheme:
A kind of dextromethorphan hydrobromide oral cavity disperses membrane, comprises dextromethorphan hydrobromide, film former, plasticizer, disintegrating agent, wetting agent, correctives, coloring agent and water.
Preferably, described dextromethorphan hydrobromide oral cavity disperses membrane also to comprise polacrilin or the polacrilin potassium of particle diameter at 50～150 μ m, and dextromethorphan hydrobromide and polacrilin or polacrilin potassium form dextromethorphan hydrobromide complex, the weight ratio of dextromethorphan hydrobromide and polacrilin or polacrilin potassium is 1:1～1:1.5, is preferably 1:1.2～1:1.4.
Preferably, described dextromethorphan hydrobromide complex is prepared by the following method:
Get dextromethorphan hydrobromide and polacrilin or polacrilin potassium according to described weight ratio; Polacrilin is suspended in sodium hydroxide or potassium hydroxide, and the weight/mol ratio of polacrilin and sodium hydroxide or potassium hydroxide is 1g:0.0025mol～1g:0.005mol; Or polacrilin potassium is suspended in water; Add dextromethorphan hydrobromide, stir lower dextromethorphan hydrobromide and polacrilin or polacrilin potassium generation adsorption reaction;
Preferred, dextromethorphan hydrobromide several times with polacrilin or polacrilin potassium generation adsorption reaction.
Further preferred, described dextromethorphan hydrobromide complex, by the following method preparation:
(1) be 1:1～1:2 according to the part by weight of polacrilin or polacrilin potassium and dextromethorphan hydrobromide, be preferably 1:1.3～1:1.5, prepare raw material; Dextromethorphan hydrobromide is divided into 2～4 parts;
(2) preparation sodium hydroxide solution, wherein liquor capacity is the more than 50 times of every part of dextromethorphan hydrobromide weight, polacrilin and sodium hydroxide weight/mol ratio are 1g:0.0025mol～1g:0.005mol; Polacrilin is added in described sodium hydroxide solution, stir 2～10 hours, preferably stir 4～8 hours, obtain suspension; Or
Polacrilin potassium is added to the water, and the volume of water is the more than 50 times of every part of dextromethorphan hydrobromide weight, stirs 1～2 hour, obtains suspension;
(3) to the ethanol and the 1 part of dextromethorphan hydrobromide that add the volume 5% of described sodium hydroxide solution or water in above-mentioned suspension, under room temperature, stir 6～12 hours; Filter, discard filtrate, retain filter cake;
(4) separately get 1 part of dextromethorphan hydrobromide water-soluble, the volume of water is the more than 50 times of dextromethorphan hydrobromide weight, and the filter cake that adds previous step to obtain stirs 6～12 hours, filters, and retains filter cake;
(5) repeating step 4 operates, until that all dextromethorphan hydrobromides all react is complete, with ethanol or ethanol and water wheels stream washing leaching cake, 50 DEG C～70 DEG C dry, pulverize 80 mesh sieves.
Dextromethorphan hydrobromide of the present invention oral cavity disperses membrane, comprises that the raw material of following weight portion is:
In 5～10 parts of the described dextromethorphan hydrobromide complex of dextromethorphan hydrobromide, film former 14-28 part, plasticizer 6-10 part, disintegrating agent 4-14 part, wetting agent 1-2 part, coloring agent 2～4 weight portions, correctives 1～3 weight portion, water 140-180 part;
Wherein, film former comprises hydroxypropyl methylcellulose; Can also comprise pregelatinized Starch;
Plasticizer comprises cetomacrogol 1000 and propylene glycol; Can also comprise pregelatinized Starch;
Disintegrating agent comprises microcrystalline Cellulose; Can also comprise low-substituted hydroxypropyl cellulose;
Wetting agent is selected from sorbitol and/or maltodextrin.
Preferably, described film former is hydroxypropyl methylcellulose, is preferably made up of hydroxypropyl methylcellulose E3 and hydroxypropyl methylcellulose E50, and weight ratio is hydroxypropyl methylcellulose E3: hydroxypropyl methylcellulose E50=5:1～7:1;
Described plasticizer is made up of cetomacrogol 1000 and propylene glycol, and weight ratio is cetomacrogol 1000: propylene glycol=2～3:1;
Described disintegrating agent is microcrystalline Cellulose;
Described wetting agent is sorbitol.
Preferably, described coloring agent is selected from coating powder; Described correctives is selected from sucralose and/or essence.
Another object of the present invention, is to provide above-mentioned dextromethorphan hydrobromide oral cavity to disperse the preparation method of membrane, comprises according to weight portion and gets each raw material, and be added to the water, dispersed with stirring is even, leaves standstill coating, cutting; Or
Get each raw material according to weight portion, described film former and plasticizer add in 1/2nd weight parts waters, are stirred to dissolve, and obtain solution A; Described dextromethorphan hydrobromide complex and remaining other adjuvant add in remaining water, and dispersed with stirring is even, obtains solution B; , mix with solution B during without bubble until solution A, stir, leave standstill, coating, cutting.
Above-mentioned two kinds of preparation methoies, preferably more easily before a kind of method.
Described dextromethorphan hydrobromide oral cavity disperses the preparation method of membrane, and when film former comprises hydroxypropyl methylcellulose E3, preferably hydroxypropyl methylcellulose E3 gradation is added to the water.
As a preferred embodiment of the present invention, the invention provides a kind of dextromethorphan hydrobromide oral cavity and disperse membrane, according to weight portion meter, raw material comprises:
The invention provides a kind of preferred dextromethorphan hydrobromide oral cavity and disperse membrane, according to weight portion meter, raw material comprises:
The present invention also provides above-mentioned preferred dextromethorphan hydrobromide oral cavity to disperse the preparation method of membrane, specifically comprises the steps:
I. get each raw material according to weight portion, described dextromethorphan hydrobromide complex is crossed 80 mesh sieves;
II. under stirring, propylene glycol, cetomacrogol 1000, sorbitol, sucralose, essence are added to the water, make to dissolve;
III. under stirring, then add 1/4th to 1/3rd hypromellose E3, make to dissolve;
IV. under stirring, add microcrystalline Cellulose and described dextromethorphan hydrobromide complex, make to be uniformly dispersed;
V. under stirring, add coating powder, hypromellose E50 and remaining hypromellose E3, make to dissolve;
VI. evacuation leaves standstill, until obviously bubble of nothing in visual observations solution;
VII. coating, film thickness is 110 μ m～130 μ m;
VIII. cutting;
IX. inner packing.
Coating powder of the present invention, it is commercial water solublity premixing auxiliary material, comprise coloring agent, hypromellose, cetomacrogol 1000, propylene glycol etc., good with other composition compatibility of pelliculae pro cavo oris of the present invention, therefore preferably using commercial coating powder as coloring agent.
Ethanol of the present invention, as there is no specified otherwise, refer to the ethanol of concentration more than 95%.
Water of the present invention, as there is no specified otherwise, refer to the water that meets preparation requirement, as purified water, distilled water etc.
Oral cavity disperses membrane except meeting on preparation the requirement of disintegration, intensity and toughness, and mouthfeel is the key factor that affects patient's compliance.Dextromethorphan hydrobromide taste is extremely bitter and have numb feeling in the tongue, therefore must take suitable method to carry out taste masking.The present invention, by following research, optimizes the technical scheme solving the problems of the technologies described above.
1. the initial option of film former
The adjuvant of pelliculae pro cavo oris comprises film former, plasticizer, disintegrating agent, wetting agent, solvent, and correctives if desired, wherein taking film former as basis; Therefore, first film former is carried out to initial option.
With regard to solvent, consider the problem such as the safety of preparation process and the consumer group's (especially child) drug safety, select the purified water that meets preparation requirement as solvent.
Taking film property, with the fissility of lining material, pliability, diaphragm character etc. for investigation index, film former is carried out to Preliminary screening.Prescription is in table 1.
Table 1 film former screening prescription (one)
Technique:
(1) get cetomacrogol 1000, the glycerol (or propylene glycol) of recipe quantity purified water stirring and dissolving recipe quantity;
(2) to the adjuvant that adds recipe quantity in above-mentioned solution, stir, observe glue phenomenon;
In the time adding rice starch, after rice starch is uniformly dispersed, keep stirring and solution being slowly heated to 80 DEG C, reach after temperature, stop heating, insulation continues to stir 5min, is cooled to room temperature;
(3) coating, places in 60 DEG C of baking ovens dry.
The experimental result of each prescription group, in table 2.
Table 2 film former results of preliminary screening
Conclusion:
(1) compared with other film former, prescription 1 film property is poor, and poor fluidity and the pectin of prescription 4 solution can not dissolve completely, and diaphragm outward appearance is bad.So get rid of the film former that disperses membrane with polyvinyl alcohol and pectin as dextromethorphan hydrobromide of the present invention oral cavity.
(2) after the gelatinizing of rice starch high temperature, easily film forming, film is more crisp.And rice starch is after high-temperature heating, then place through the long period cooling, age of starch, whole system is easily hardened, embrittlement, exists moisture the problem such as easily to separate out.Therefore rice starch is not suitable for using as film former separately.
(3) hypromellose E3 and E50, polyvinyl alcohol (4-88) and novel adjuvant Kollicoat IR(polyvinyl alcohol-polyethyleneglycol-graft copolymer) moulding property all better, and diaphragm and lining material are all easily peeled off, therefore above-mentioned three kinds of materials are as candidate's film former of pelliculae pro cavo oris of the present invention.
But when above-mentioned three kinds of independent film forming of film former, the toughness of diaphragm is excessive, and disintegration time is longer, therefore add appropriate rice starch to regulate fragility and the disintegration of diaphragm.Add active component---dextromethorphan hydrobromide, after investigation adds solid content, on the impact of diaphragm outward appearance and film property simultaneously.Specifically write out a prescription in table 3.
Table 3 film former screening prescription (two)
Prescription 1 and 3 adopts following technique-1, and prescription 2 adopting process-2, prepare diaphragm, observe glue character, investigate film property, diaphragm outward appearance, stability and mouthfeel.
Technique-1:
(1) recipe quantity dextromethorphan hydrobromide is stirred and is dissolved in recipe quantity glycerol, heating for dissolving (60 DEG C of water-baths);
(2) get 45ml water, add polyvinyl alcohol (4-88) or the Kollicoat IR of recipe quantity, heating (60 DEG C of water-baths), stirring and dissolving.After polyvinyl alcohol (4-88) or the whole dissolvings of Kollicoat IR, leave standstill and be cooled to room temperature;
(3) get 15ml water, dissolve recipe quantity cetomacrogol 1000, until completely dissolved, add recipe quantity sucrose, stirring and dissolving;
(4), at 60 DEG C of water-baths, the solution that step 3 is obtained is poured in the solution that step 1 obtains, heated and stirred;
(5) bubble-free solution step 2 being obtained is poured in the solution that upper step obtains, heated and stirred (60 DEG C of water-baths);
(6) after above-mentioned solution mix homogeneously, add the rice starch of recipe quantity, stirring at room temperature 30min, protects and stirs and be slowly heated to 80 DEG C, stops heating, continues insulated and stirred 5min, obtains glue;
(7) glue is cooled to room temperature;
(8) coating, places in 60 DEG C of baking ovens dry.
Technique-2:
(1) get 60ml purified water, respectively cetomacrogol 1000, propylene glycol and the sucrose of stirring and dissolving recipe quantity;
(2) after above-mentioned adjuvant dissolves, stir the hypromellose E3 and the E50 that add recipe quantity, leave standstill;
(3) get recipe quantity rice starch and join in above-mentioned solution, stirring at room temperature 30min, keeps stirring and being slowly heated to 80 DEG C (solution temperatures), stops heating, continues insulated and stirred 5min;
(4) dextromethorphan hydrobromide that adds recipe quantity after the solution obtaining until upper step is cooled to room temperature, stirs, and leaves standstill, and obtains glue;
(5) coating, places in 60 DEG C of baking ovens and dries.
Experimental result is in table 4.
Table 4 film former the selection result (two)
Result shows:
Outward appearance when (1) three kind of diaphragm is initial is all better, and pliability is strong;
(2) the prepared diaphragm of polyvinyl alcohol (4-88) and Kollicoat IR is separated out at the long-time fuel-displaced and adularescent crystal in rear surface of placing, and supposition may be dextromethorphan hydrobromide.The prepared diaphragm of hypromellose E3 and E50 is long-time place after without significant change.
(3) all first sweet rear hardships of all diaphragms.
Conclusion:
To dextromethorphan hydrobromide pelliculae pro cavo oris of the present invention, polyvinyl alcohol (4-88) and Kollicoat IR are not desirable filmogens.Therefore, optimize the main film former that hypromellose E3 and E50 are pelliculae pro cavo oris of the present invention.
In addition, after many people taste, find, all there is the first phenomenon of sweet rear hardship in all diaphragms, the mouthfeel that only adds correctives to be not enough to improve pelliculae pro cavo oris of the present invention is described.Therefore must select suitable masking methods.
2. the investigation of masking methods
Because simple correctives cannot improve the mouthfeel of dextromethorphan hydrobromide, therefore consider with polacrilin or polacrilin potassium its taste masking.
Polacrilin or polacrilin potassium are water-insoluble fine particle, its diameter is extremely important to oral cavity dispersion membrane agent, and granule is too large, and patient is in the time taking medicine, in mouthful, can produce a kind of " grains of sand sense ", therefore polacrilin and the polacrilin potassium of preferred particulates diameter between 50-150 μ m.
By preliminary experiment, find that 100ml water+5ml ethanol (accounting for water volume 5%) can dissolve 2.0g dextromethorphan hydrobromide completely, therefore, in experiment below, dissolves dextromethorphan hydrobromide mainly with the method greatly.
2.1 odor mask kinds, consumption are investigated
Design drug loading, taste masking effect and the impact of pre-treatment on polacrilin medicine carrying effect on dextromethorphan hydrobromide of following the effects polacrilin and polacrilin potassium.
Experimental design is in table 5.
Table 5 odor mask is investigated experimental design
Prepare by the following method polacrilin or polacrilin potassium dextromethorphan hydrobromide complex:
Complex preparation method A(1-5 group):
(1) alkali pre-treatment
Ratio according to every gram of polacrilin by 0.01mol naoh treatment, mixes the polacrilin of recipe quantity with the sodium hydroxide solution of 100ml respective concentration, stir 1 hour, obtains polacrilin suspension;
(2) add recipe quantity dextromethorphan hydrobromide and 5ml ethanol (account for sodium hydroxide solution volume 5%), stirred overnight at room temperature;
(3) sucking filtration, collects filtrate;
(4) water cleans complex three times, each water consumption is weight resin 3 times, collect cleanout fluid, merge with the filtrate of upper step;
(4) dextromethorphan hydrobromide complex is placed in 60 DEG C of baking ovens and is dried, test mouthfeel;
(5) measure dextromethorphan hydrobromide content in filtrate according to high performance liquid chromatography (two annex V D of Chinese Pharmacopoeia version in 2010), calculate drug loading.
Complex preparation method B (the 6th group)
(1) getting purified water 100ml mixs homogeneously with 5ml ethanol; Add the dextromethorphan hydrobromide of recipe quantity, after principal agent all dissolves, add the polacrilin potassium of 3.0g, stirring is spent the night;
(2)～(4) are same with (3)～(5) of technique A.
Investigate index taking dextromethorphan hydrobromide content in filtrate as drug loading, taking mouthfeel as taste masking effectiveness indicator.The results are shown in Table 6.
Table 6 odor mask kind & drug loading is investigated result
Result shows: polacrilin and the polacrilin potassium of the same amount of process alkali treatment, do not have difference to the drug loading of dextromethorphan hydrobromide.Polacrilin consumption is larger, and drug loading is larger.
Conclusion:
(1) polacrilin and polacrilin potassium can be served as the odor mask of dextromethorphan hydrobromide of the present invention.
(2) weight ratio of dextromethorphan hydrobromide and polacrilin or polacrilin potassium is between 1:1～1:2, and drug loading is higher; Lower than this ratio, drug loading obviously reduces.The factors such as considering cost, more preferably the weight ratio of dextromethorphan hydrobromide and polacrilin or polacrilin potassium is 1:1.3～1:1.5.
The dextromethorphan hydrobromide complex that adopts said method to prepare, although bitterness weakens to some extent, does not still reach gratifying effect.Even if strengthen the consumption of odor mask, also cannot improve taste masking effect.Therefore, also need masking methods to do further research.
Polacrilin is combined with dextromethorphan hydrobromide and is generated the process of complex, relates to alkali pre-treatment, medicine carrying mode, complex and cleans, and therefore above-mentioned several aspects is all examined or check, to reach best taste masking effect.
The optimization of 2.2 alkali pre-treatments
2.2.1 the investigation of alkali kind
The alkalescence of potassium hydroxide is stronger, therefore compares the pre-treatment effect of sodium hydroxide and potassium hydroxide.
Dextromethorphan hydrobromide complex preparation technology:
(1) prepare respectively 1mol/L sodium hydroxide solution and 1mol/L potassium hydroxide solution;
(2) get respectively the above-mentioned sodium hydroxide solution of 80ml and potassium hydroxide solution, be diluted to 300ml by purified water, add respectively polacrilin 8.0g, stir 1h;
(3) add respectively 5% ethanol to stir, add dextromethorphan hydrobromide 6.0g, stirring is spent the night;
(4) filter respectively, collect filtrate, filter cake cleans three times with ethanol, and each 50ml merges with aforementioned filtrate;
(5) complex after sucking filtration is placed in 60 DEG C of baking ovens dry;
(6) photograph high performance liquid chromatography (two annex V D of Chinese Pharmacopoeia version in 2010) is measured the content of dextromethorphan hydrobromide in filtrate.
The results are shown in Table 7.
Table 7 alkali kind is investigated result
As shown in Table 7: with the content of dextromethorphan hydrobromide in filtrate after potassium hydroxide treatment apparently higher than the sample size after naoh treatment.
Conclusion:
The alkalescence of the drug loading of polacrilin and pre-treatment alkali liquor is strong and weak without obvious dependency.With after potassium hydroxide treatment polacrilin, the drug loading of polacrilin decreases on the contrary.Therefore preferred sodium hydroxide pre-treatment polacrilin.
2.2.2 alkali consumption and processing time are investigated
2.2.2.1 alkali consumption is investigated
Experimental technique:
(1) get respectively the sodium hydroxide solution of the 1mol/L of 20ml/40ml/80ml, be diluted to 300ml by purified water, add respectively 8.0g polacrilin, stirring and evenly mixing 1h;
(2) add respectively the ethanol of 5% (percent by volume) to stir, add 6.0g dextromethorphan hydrobromide, stirring is spent the night;
(3) every group of sample filters respectively, and filter cake cleans three times with ethanol, each 50ml;
(4) complex after sucking filtration is placed in 60 DEG C of baking ovens dry;
(5) photograph high performance liquid chromatography (two annex V D of Chinese Pharmacopoeia version in 2010) is measured the content of dextromethorphan hydrobromide in complex.
The results are shown in Table 8.
Table 8 pre-treatment alkali liquor consumption is investigated result
Result shows: the consumption of sodium hydroxide is the impact without significance on the medicine carrying effect of polacrilin.The factors such as integrated cost are considered, when pre-treatment, can reduce the consumption of sodium hydroxide, and weight (g)/mole (mol) of preferred polacrilin and sodium hydroxide is than being 1:0.0025～1:0.005.
2.2.2.2 the pre-treatment time is investigated
Taking the pH value of solution and electrical conductivity as detecting index, until pH value and conductivity are stable, to determine the best pre-treatment time.
Test method:
Get the sodium hydroxide solution of 20ml1mol/L, be diluted to 300ml by purified water, add 8.0g polacrilin, stir; Every 1-2 hour, pH value and the electrical conductivity of a solution of detection.
The results are shown in Table 9.
The table 9 pre-treatment time is investigated result
Result shows: after 2 hours, pH value and the electrical conductivity of sample solution reach balance.
Conclusion:
After sodium hydroxide reacts 2 hours with polacrilin, the pH value of sample and electrical conductivity substantially no longer change, and reach balance.Consider and make polacrilin and sodium hydroxide complete reaction, preferably the pre-treatment time is 4～8 hours, more preferably 6 hours.
2.2.3 the investigation of cleaning solvent
Experimental design is in table 10.
Table 10 cleaning solution is investigated experimental design
*: volume ratio, is used second alcohol and water in turn when cleaning.
Experimental technique:
(1) get respectively the sodium hydroxide solution of 80ml1mol/L, be diluted to 300ml by purified water, add 15ml ethanol (account for after dilution sodium hydroxide solution volume 5%) mix homogeneously, add 8.0g polacrilin, stir 1 hour;
(2) in above-mentioned suspension, add respectively 6.0g dextromethorphan hydrobromide, stirring is spent the night;
(3) filter respectively, collect filtrate; Filter cake is respectively according to cleaning shown in table 10;
(4) dextromethorphan hydrobromide complex is placed in 60 DEG C of baking ovens and is dried, investigate mouthfeel;
(5) content of dextromethorphan hydrobromide in detection filtrate.
The results are shown in Table 11.
Table 11 cleaning solution is investigated experimental result
Result shows: with ethanol or alcohol water cleaning resin, the dextromethorphan hydrobromide content in filtrate is higher, and the mouthfeel of complex is improved.
Conclusion:
Taking water as cleaning solvent, in filtrate, the content of dextromethorphan hydrobromide is cleaning solvent, mouthfeel hardship lower than ethanol or alcohol water, illustrates that water can not will elute for free dextromethorphan hydrobromide well.Ethanol and water wheels stream eluting can reach the effect same with ethanol, but because eluting number of times is more, commercial production complex steps, so be not preferred method.Therefore preferably use ethanol as cleaning solvent.
2.3 optimizing factors checkings
Comprehensive each factor of having optimized above, prepares dextromethorphan hydrobromide complex, investigates taste masking effect.
Test method:
(1) get the sodium hydroxide solution 20ml of 1mol/L, be diluted to 300ml by purified water, add 15ml ethanol (account for after dilution sodium hydroxide solution volume 5%) ethanol mix homogeneously, add 8.0g polacrilin, stir 6 hours;
(2) in above-mentioned suspension, add 6.0g dextromethorphan hydrobromide, stirring is spent the night;
(3) filter, collect filtrate; Filter cake cleans three times with ethanol, each 50ml;
(4) dextromethorphan hydrobromide complex is placed in 60 DEG C of baking ovens and is dried, investigate mouthfeel.
Aforesaid operations is parallel to carry out three times.
Result:
Taste through many people, though the mouthfeel of complex can accept, still more bitter.The applicable crowd who considers pelliculae pro cavo oris of the present invention is mainly child, and present taste masking effect is unsatisfactory.
The investigation of 2.4 medicine carrying modes
Can research above be all carried out in single medicine carrying mode, therefore investigate repeatedly medicine carrying method and be superior to single medicine carrying.
Experimental technique
Technique 1:
(1) get the sodium hydroxide solution 20ml of 1mol/L, be diluted to 300ml by purified water, add the polacrilin of 8.0g, stirring and evenly mixing 6h;
(2) add the ethanol of 15ml to stir, add 6.0g dextromethorphan hydrobromide, stirring is spent the night;
(3) filter, filter cake cleans three times with ethanol, each 50ml;
(4) complex after cleaning is placed in 60 DEG C of baking ovens dry;
(5) detect the content of dextromethorphan hydrobromide in complex, and investigate mouthfeel.
Technique 2:
(1) get the sodium hydroxide solution 20ml of 1mol/L, be diluted to 140ml by purified water, add the polacrilin of recipe quantity, stirring and evenly mixing 6h;
(2) add the ethanol of 6ml and the dextromethorphan hydrobromide of 2.0g, stir 12 hours, filter;
(3) dextromethorphan hydrobromide of 2.0g is stirred and is dissolved in 140ml water, then the filter cake that upper step is obtained joins in Dextromethorphan Hydrobromide Solution, stirs filtration 10 hours;
(4) dextromethorphan hydrobromide of 2.0g is stirred and is dissolved in 140ml water, then the filter cake that upper step is obtained joins in Dextromethorphan Hydrobromide Solution, stir 10 hours;
(5) sucking filtration; Filter cake cleans three times with ethanol, each 50ml;
(6) complex after cleaning is placed in 60 DEG C of baking ovens dry;
(7) content of dextromethorphan hydrobromide in detection complex, calculates drug loading, and investigates mouthfeel.
The results are shown in Table 12.
Table 12 medicine carrying mode is investigated result
Result shows: repeatedly the drug loading of medicine carrying method (91.21%) is higher than the drug loading (88.44%) of single medicine carrying method, but complex sensory difference prepared by two kinds of methods is obvious.
Conclusion:
Repeatedly the standby complex drug loading of medicine carrying legal system is high, and mouthfeel is good.Therefore, preferred medicine carrying method repeatedly.
The checking of 2.5 preferred masking methods
Optimized each influence factor of masking methods by above experiment: odor mask is polacrilin or polacrilin potassium; Polacrilin pre-treatment test solution is sodium hydroxide, and the weight/mol ratio of polacrilin and sodium hydroxide is 1g:0.0025mol～1g:0.005mol, and the pre-treatment time is 2～10 hours; The part by weight of polacrilin or polacrilin potassium and principal agent is 1:1.3～1:1.5; Medicine carrying mode is multiple adsorb; Cleaning solvent is ethanol or second alcohol and water, repeatedly cleans.
The masking methods optimizing is:
(1) be 1:1.3～1:1.5 according to the part by weight of polacrilin or polacrilin potassium and dextromethorphan hydrobromide, prepare raw material; Dextromethorphan hydrobromide is divided into 2～4 parts;
(2) preparation sodium hydroxide solution, wherein liquor capacity is the more than 50 times of every part of dextromethorphan hydrobromide weight, polacrilin and sodium hydroxide weight/mol ratio are 1g:0.0025mol～1g:0.005mol; Polacrilin is added in described sodium hydroxide solution, stir 4～8 hours, obtain suspension; Or
Polacrilin potassium is added to the water, and the volume of water is the more than 50 times of every part of dextromethorphan hydrobromide weight, stirs 1～2 hour, obtains suspension;
(3) to the ethanol and the 1 part of dextromethorphan hydrobromide that add the volume 5% of described sodium hydroxide solution or water in above-mentioned suspension, under room temperature, stir 6～12 hours; Filter, discard filtrate, retain filter cake;
(4) separately get 1 part of dextromethorphan hydrobromide water-soluble, the volume of water is the more than 50 times of dextromethorphan hydrobromide weight, and the filter cake that adds previous step to obtain stirs 6～12 hours, filters, and retains filter cake;
(5) repeating step 4 operates, until that all dextromethorphan hydrobromides all react is complete, with ethanol or ethanol and water wheels stream washing leaching cake, 50 DEG C～70 DEG C dry, pulverize 80 mesh sieves.
Taste masking effect by the above-mentioned method for optimizing of following experimental verification:
(1) configuration 1mol/L sodium hydroxide solution: get the 56.0g sodium hydroxide stirring and dissolving that adds water, to be dissolvedly add water to 1400ml after completely;
(2) sodium hydroxide solution of the 1mol/L of 1400ml is diluted to 9800ml by purified water, to be mixed evenly after, add 560g polacrilin, stir 6 hours;
(3) in the good solution of above-mentioned suspendible, add the dextromethorphan hydrobromide of 490ml ethanol and 140.0g, under room temperature, stir 12 hours; Sucking filtration, discards filtrate, retains filter cake;
(4) dextromethorphan hydrobromide of 140.0g is dissolved in 9800ml purified water to stirring and dissolving; After dextromethorphan hydrobromide dissolves completely, the filter cake that adds step to obtain; Under room temperature, stir 10 hours; Sucking filtration, discards filtrate, retains filter cake;
(5) dextromethorphan hydrobromide of 140.0g is dissolved in 9800ml purified water to stirring and dissolving; After dextromethorphan hydrobromide dissolves completely, the filter cake that adds step to obtain; Under room temperature, stir 10 hours;
(6) question response completely after, carry out sucking filtration, clean filter cake three times, each 3500ml with ethanol;
(7) complex after sucking filtration is placed in 60 DEG C of baking ovens dry;
(8) content of dextromethorphan hydrobromide in detection complex, calculates drug loading, and investigates mouthfeel.
Experimental result is in table 13.
Table 13 masking methods the result
Conclusion:
Above result shows, the dextromethorphan hydrobromide complex of preparing according to above method, and drug loading is high, and mouthfeel is good, illustrates that above formulation and technology is feasible.
Optimizing on dextromethorphan hydrobromide complex preparation technology's basis, film-forming process is being investigated with preferred.
3. the investigation of film-forming process
Below dextromethorphan hydrobromide complex used in research, all prepares according to " 2.5 " lower described method, and its consumption is all by dextromethorphan hydrobromide.
The investigation of 3.1 quantity of solvent
Experimental design is as shown in table 14, prepares by the following method diaphragm.
Table 14 film-forming process quantity of solvent is investigated experimental design
Preparation method:
(1) get the hot purified water of 1/2 recipe quantity, the propylene glycol of stirring and dissolving recipe quantity, cetomacrogol 1000, hypromellose E50 and hypromellose E3, leave standstill, and bubble removing, obtains solution 1;
(2) get the purified water that remains 1/2 recipe quantity, add successively sucralose, essence, sorbitol, coating powder, microcrystalline Cellulose, dextromethorphan hydrobromide complex, pregelatinized Starch, the low-substituted hydroxypropyl cellulose of recipe quantity, stir, obtain solution 2;
(3), join in solution 2 during without bubble until solution 1, stir, make it become uniform suspension solution;
(4) above-mentioned suspension solution sample is heated to 80 DEG C, gelatinizing 7min, then naturally cools to room temperature;
(5) respectively by the suspension solution coating before gelatinizing and after gelatinizing, diaphragm is placed in 60 DEG C of baking ovens and is dried.
The results are shown in Table 15.
Table 15 quantity of solvent is investigated experimental result
Result shows: quantity of solvent is larger, and the bubble in viscous solution is easily removed.After gelatinizing, the viscosity of solution is recovered, but diaphragm outward appearance, suppleness, fragility and disintegrate after coating do not have the variation of significance.
Conclusion:
(1), in the time that quantity of solvent is larger, the bubble in the thick liquid of coating is easily removed.Therefore determine that while disperseing membrane in preparation oral cavity, quantity of solvent is 160ml left and right (1000);
(2) due to before and after gelatinizing, there is not the variation of significance in the characteristic index such as outward appearance, fragility of diaphragm, therefore thinks that gelatinizing step can save.
3.2 compound methods are investigated
The compound method of film forming glue has separately preparation and mixed preparing.Separately compound method sees above " preparation method " under " 3.1 " item.Mixed preparation method is: in layoutprocedure, according to sequencing, supplementary material is added in solution, specifically comprise the steps:
(1) get 160ml purified water, successively the propylene glycol of stirring and dissolving recipe quantity, cetomacrogol 1000, sorbitol, sucralose, strawberry essence;
(2) after above-mentioned adjuvant dissolves completely, add successively dextromethorphan hydrobromide complex, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, the pregelatinized Starch of recipe quantity, dispersion stirs;
(3) add coating powder, hypromellose E3, the hypromellose E50 of recipe quantity, stirring and dissolving, hold over night, bubble removing;
(4) in range estimation solution during without obvious bubble, coating, diaphragm is placed in 60 DEG C of baking ovens and is dried.
Prepare two parts of raw materials according to " 3.1 " lower prescription 2, prepare diaphragm according to separating preparation and mixed preparation method respectively, the results are shown in Table 16.
Table 16 compound method is investigated result
Result shows: solution and diaphragm that separately prepared by preparation and two kinds of methods of mixed preparing are observed from outward appearance, without the difference of significance.
Conclusion:
For saving material, equipment and time, preferably mixed preparing legal system is for membrane of the present invention, to adapt to industrialized great production.
3.3 film forming prescriptions are investigated
Because the diaphragm of preparing in aforementioned research is all thinner, the diaphragm drug loading of unit are is little; And fragility is large, is unfavorable for transport and stores.Therefore designed multiple prescription with the performance Formulation that improves diaphragm in table 17.
Table 17 film forming prescription is investigated experimental design
Preparation method: according to the lower mixing preparation method of " 3.2 " item.
The results are shown in Table 18.
Table 18 film forming prescription is investigated experimental result
Conclusion:
(1) prescription 2 samples are because diaphragm is thin, and sheet is heavy less, and in coating process, sheet is heavy wayward, and diaphragm fragility is larger, in cutting process, likely causes the breakage of diaphragm; Write out a prescription 3 samples, prescription 4 sample diaphragm thickness are moderate, and in coating, dry and cutting process, diaphragm outward appearance is more complete.Because 4 weights of sample are larger, coating process is easily controlled, and therefore writes out a prescription 4 for comparatively suitable membrane prescription.
(2) because pregelatinized Starch can obtain gelatinized corn starch in cold water, low-substituted hydroxypropyl cellulose also has certain viscosity, thereby make total viscosity of adjuvant excessive, causing water-fast solid adjuvant material and dextromethorphan hydrobromide complex to disperse inhomogeneous, all there is " scratch " of thickness inequality in membrane surface.Therefore consider these two kinds of adjuvants all to remove.
(3) in order to solve " scratch " problem, the adjustment of first writing out a prescription of trying.
3.4 " scratch " solution
Taking above-mentioned prescription 4 as basis, design multiple prescription, comprise usage ratio, the dextromethorphan hydrobromide complex micronization etc. of adjusting each adjuvant, solve the prescription of " scratch " to optimization.Formulation is in table 19.
Table 19 " scratch " solves Formulation
Preparation technology:
(1) get 480ml purified water, successively the propylene glycol of stirring and dissolving recipe quantity, cetomacrogol 1000, sorbitol, sucralose, essence;
(2) after above-mentioned adjuvant dissolves completely, add successively recipe quantity dextromethorphan hydrobromide complex, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose (if any), pregelatinized Starch (if any), dispersed with stirring is even;
(3) add coating powder, hypromellose E3, the hypromellose E50 of recipe quantity, stirring and dissolving, hold over night;
(4) in visual observations solution during without obvious bubble, coating, diaphragm is placed in 60 DEG C of baking ovens and is dried.
Experimental result:
(1), although prescription 7～10 is write out a prescription 5 and 6 has clear improvement, all there is " scratch " in 5～10 the diaphragm of writing out a prescription; Illustrate that adjusting prescription can not solve " scratch " problem;
(2) dextromethorphan hydrobromide complex micronization can not improve " scratch ".
Easily assemble in aqueous solution owing to finding complex in test, so consider to adjust the addition sequence of supplementary material on the basis of prescription 10, object is the gathering that reduces composite particles, addition sequence is: solubility adjuvant (propylene glycol, cetomacrogol 1000, sorbitol, sucralose, essence), coating powder, hypromellose E3, hypromellose E50, complex, microcrystalline Cellulose.
To write out a prescription 10 as basis, prepare diaphragm by being prepared as follows technique:
Preparation technology I:
(1) get 480ml purified water, successively the propylene glycol of stirring and dissolving recipe quantity, cetomacrogol 1000, sorbitol, sucralose, essence;
(2) after above-mentioned adjuvant dissolves completely, stir the coating powder that adds recipe quantity, be uniformly dispersed;
(3) add successively hypromellose E3, the hypromellose E50 of recipe quantity, stirring and dissolving; (4) after hypromellose E3 and hypromellose E50 dissolve completely, add dextromethorphan hydrobromide complex and the microcrystalline Cellulose of recipe quantity, dispersed with stirring is even;
(5) in perusal solution during without obvious bubble, coating.
(6) cutting, packaging.
Result: diaphragm is without " scratch ", and uniform particles distributes.But in process for preparation, find, after stirring adds hypromellose E3, hypromellose E50 and coating powder, to produce a large amount of bubbles, cause complex and microcrystalline Cellulose to be suspended on bubble, need to leave standstill for a long time suitability for industrialized production difficulty.
Therefore consider hypromellose E3 and hypromellose E50 separately to add, to overcome the problem that produces bubble.
Preparation technology II:
(1) get 480ml purified water, successively the propylene glycol of stirring and dissolving recipe quantity, cetomacrogol 1000, sorbitol, sucralose, essence;
(2) after above-mentioned adjuvant dissolves completely, the hypromellose E3 of stirring and dissolving recipe quantity;
(3) until completely dissolved, add successively microcrystalline Cellulose and the dextromethorphan hydrobromide complex of recipe quantity, dispersed with stirring is even;
(4) stir the coating powder and the hypromellose E50 that add recipe quantity, dissolve;
(5) in visual observations solution during without obvious bubble, coating;
(6) cutting, packaging.
Result: diaphragm is without " scratch "; But in layoutprocedure, find in the time adding the hypromellose E3 of recipe quantity, must leave standstill a period of time, just can add other supplementary materials, otherwise also can produce a large amount of bubbles.Therefore the hypromellose E3 that considers first to add 1/3 recipe quantity, then adds other supplementary materials successively.
Again adjust preparation technology.
Preparation technology III:
(1) get 480ml purified water, successively the propylene glycol of stirring and dissolving recipe quantity, cetomacrogol 1000, sorbitol, sucralose, essence;
(2) after above-mentioned adjuvant dissolves completely, the hypromellose E3 of stirring and dissolving 1/3 recipe quantity; (3) after hypromellose E3 dissolves completely, add successively microcrystalline Cellulose and the dextromethorphan hydrobromide complex of recipe quantity, dispersed with stirring is even;
(4) add the coating powder, hypromellose E50 of recipe quantity and remaining 2/3 hypromellose E3, stirring and dissolving;
(5) leave standstill, in visual observations solution during without obvious bubble, coating;
(6) cutting, packaging.
Result: solution viscosity is suitable, and the hypromellose E3, the E50 that finally add all can dissolve completely.Solution is coated with, and diaphragm is without " scratch ", and uniform particles distributes.(≤30s) conforms with the regulations disintegration
By above-mentioned research and experiment, finally optimize prescription and the preparation technology of dextromethorphan hydrobromide pelliculae pro cavo oris of the present invention.That is:
Prescription:
Technique:
(1) configuration 175ml sodium hydroxide solution, making the weight/mol ratio of polacrilin and sodium hydroxide is 1:0.0025, adds the polacrilin of recipe quantity, stirs 6 hours; Or
Get the polacrilin potassium of recipe quantity, add 175ml water, stir 1～2 hour;
(2) in the good solution of above-mentioned suspendible, add the ethanol of 8.75ml and the dextromethorphan hydrobromide of 2.5g, under room temperature, stir, react approximately 10～12 hours.After question response is complete, carry out sucking filtration, discard sucking filtration liquid, retain filter cake;
(3) dextromethorphan hydrobromide of 2.5g is dissolved in 175ml purified water to stirring and dissolving.After dextromethorphan hydrobromide dissolves completely, add under above-mentioned filter cake room temperature and stir, react approximately 10～12 hours.After question response is complete, carry out sucking filtration, discard sucking filtration liquid, retain filter cake;
(4) dextromethorphan hydrobromide of 2.5g is dissolved in 175ml purified water to stirring and dissolving.After dextromethorphan hydrobromide dissolves completely, add above-mentioned filter cake stirring at room temperature, react approximately 10～12 hours;
(5) question response completely after, carry out sucking filtration, clean resin with the ethanol of 62.5ml afterwards;
(6) dextromethorphan hydrobromide complex is placed in 60 DEG C of baking ovens dry;
(7) dextromethorphan hydrobromide complex is pulverized, and crosses 80 mesh sieves;
(8) detect dextromethorphan hydrobromide complex content;
(9) get 160ml purified water, successively the propylene glycol of stirring and dissolving recipe quantity, cetomacrogol 1000, sorbitol, sucralose, essence;
(10) after above-mentioned adjuvant dissolves completely, the hypromellose E3 of stirring and dissolving 6.2g;
(11) after hypromellose E3 dissolves completely, add successively microcrystalline Cellulose and the dextromethorphan hydrobromide complex of recipe quantity, dispersed with stirring is even;
(12) add the hypromellose E3 of coating powder, hypromellose E50 and the remaining 12.4g of recipe quantity, stirring and dissolving;
(13) evacuation leaves standstill, in range estimation solution during without obvious bubble, and coating;
(14) cutting;
(15) packaging.
4. best prescription and process certification
According to above-mentioned definite best prescription and preparation method, prepare dextromethorphan hydrobromide complex by polacrilin and dextromethorphan hydrobromide, then prepare 20000 (lot numbers: 121001) of sample, taking outward appearance, water activity, content, uniformity of dosage units, dissolution and related substance as investigating index, evaluate.The results are shown in Table 20.
Table 20 best prescription and process certification result
Above-mentioned experimental result shows, sample prepared by above-mentioned formulation and technology, and outward appearance is neat, color and luster homogeneous, edge is complete.Pliability, fragility, content, uniformity of dosage units, water activity, dissolution and the related substance of diaphragm all conform with the regulations.So determine that above-mentioned prescription and technique are the most preferred embodiment of the present invention.
Dextromethorphan hydrobromide pelliculae pro cavo oris provided by the invention, except meeting the General Requirements of membrane, mouthfeel is good, is easily accepted by patient, improves patient's compliance.And by optimizing preparation technology, making diaphragm smooth in appearance, attractive in appearance, active component is more evenly distributed.
Detailed description of the invention
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these embodiment are only for the present invention is described, the scope that it does not limit the present invention in any way.
Experimental technique in following embodiment, if no special instructions, is conventional method.Medicinal raw material, reagent material etc. used in following embodiment, if no special instructions, is commercially available purchase product.Wherein, part supplementary material purchase situation is as follows:
Dextromethorphan hydrobromide (manufacturer: Divis Laboratories Limited) is bought from Zhaoqing Ding Kang pharmaceutcal corporation, Ltd
Polacrilin (manufacturer: Rohm and Haas France S.A.S.) is bought from Beijing Feng Lijingqiu commerce and trade Co., Ltd
Polacrilin potassium (manufacturer: Rohm and Haas France S.A.S.) is bought from Beijing Feng Lijingqiu commerce and trade Co., Ltd
Hypromellose E3(manufacturer: Dow Chemical) buy from Shanghai Ka Lukang packaging technique company limited
Hypromellose E50(manufacturer: Dow Chemical) buy from Shanghai Ka Lukang packaging technique company limited
Cetomacrogol 1000 is bought from Hu'nan Erkang Pharmaceutical Co., Ltd.
Propylene glycol is bought from Hu'nan Erkang Pharmaceutical Co., Ltd.
Sorbitol (manufacturer: Nanning chemical pharmacy company limited) is bought from Beijing Feng Lijingqiu commerce and trade Co., Ltd
Microcrystalline Cellulose (manufacturer: FMC BioPolymer) is bought from Ai Minsi Supreme Being (Shanghai) trade Co., Ltd
Coating powder is bought from Shanghai Colorcon Coating Technology Co., Ltd
embodiment 1a kind of dextromethorphan hydrobromide oral cavity disperses membrane
Prescription is in table 21 and 22.
Preparation by the following method:
1. the sodium hydroxide solution of the 1mol/L of 25ml is diluted to 175ml by purified water, and to be mixed evenly after, add the polacrilin of recipe quantity, the weight/mol ratio of polacrilin and sodium hydroxide is 1g:0.0025mol, stirs 6 hours;
2. in the good solution of above-mentioned suspendible, add the dextromethorphan hydrobromide of 8.75ml ethanol and 2.5g, stirring at room temperature, reacts 12 hours; Sucking filtration, discards filtrate, retains filter cake;
3. the dextromethorphan hydrobromide of 2.5g is dissolved in 175ml purified water to stirring and dissolving.After dextromethorphan hydrobromide dissolves completely, add above-mentioned filter cake to react, stirring at room temperature, reacts 10 hours; Sucking filtration, discards filtrate, retains filter cake;
4. the dextromethorphan hydrobromide of 2.5g is dissolved in 175ml purified water to stirring and dissolving.After dextromethorphan hydrobromide dissolves completely, add above-mentioned filter cake to react, stirring at room temperature, reacts 10 hours;
Question response completely after, carry out sucking filtration, clean resin with the ethanol of 62.5ml afterwards;
6. dextromethorphan hydrobromide complex is put into 60 DEG C of baking ovens dry;
7. dextromethorphan hydrobromide complex is pulverized, crossed 80 mesh sieves;
8. detect the content of dextromethorphan hydrobromide complex;
9. get recipe quantity purified water, successively the propylene glycol of stirring and dissolving recipe quantity, cetomacrogol 1000, sorbitol, sucralose, strawberry essence;
10. after above-mentioned adjuvant dissolves completely, stirring and dissolving 6.2g hypromellose E3;
11. after hypromellose E3 dissolves completely, adds successively microcrystalline Cellulose and the dextromethorphan hydrobromide complex of recipe quantity, and dispersed with stirring is even;
12. add coating powder, hypromellose E50 and the remaining hypromellose E3 of recipe quantity, stirring and dissolving;
13. evacuation leave standstill, until obviously bubble of nothing in visual observations solution;
14. coatings;
15. cuttings;
16. inner packings.
embodiment 2a kind of dextromethorphan hydrobromide oral cavity disperses membrane
Prescription is in table 21 and 22.
By the step preparation similar to embodiment 1, difference is:
1. the sodium hydroxide solution of the 1mol/L of 50ml is diluted to 175ml by purified water, the weight/mol ratio of polacrilin and sodium hydroxide is 1g:0.005mol, stirs 4 hours;
2. stir 6 hours;
3. stir 8 hours;
5. clean with 32.5ml ethanol and 30ml water wheels stream;
10. the hypromellose E3 of stirring and dissolving 4.5g.
embodiment 3a kind of dextromethorphan hydrobromide oral cavity disperses membrane
Prescription is in table 21 and 22.
Preparation by the following method:
1. the sodium hydroxide solution of the 1mol/L of 35ml is diluted to 175ml by purified water, and to be mixed evenly after, add the polacrilin of recipe quantity, the weight/mol ratio of polacrilin and sodium hydroxide is 1g:0.0025mol, stirs 10 hours;
2. in the good solution of above-mentioned suspendible, add the dextromethorphan hydrobromide of 8.75ml ethanol and 2.5g, stirring at room temperature, reacts 10 hours; Sucking filtration, discards filtrate, retains filter cake;
3. the dextromethorphan hydrobromide of 2.5g is dissolved in 175ml purified water to stirring and dissolving.After dextromethorphan hydrobromide dissolves completely, add above-mentioned filter cake to react, stirring at room temperature, reacts 8 hours; Sucking filtration, discards filtrate, retains filter cake;
4. the dextromethorphan hydrobromide of 2.5g is dissolved in 175ml purified water to stirring and dissolving.After dextromethorphan hydrobromide dissolves completely, add above-mentioned filter cake to react, stirring at room temperature, reacts 8 hours;
5. the dextromethorphan hydrobromide of 2.5g is dissolved in 175ml purified water to stirring and dissolving.After dextromethorphan hydrobromide dissolves completely, add above-mentioned filter cake to react, stirring at room temperature, reacts 8 hours;
Question response completely after, carry out sucking filtration, clean resin by 32.5ml ethanol and 30ml purified water afterwards;
7～10. identical with step 6～9 of embodiment 1;
11. after above-mentioned adjuvant dissolves completely, stirring and dissolving 7g hypromellose E3;
12.～17. is identical with step 11～16 of embodiment 1.
embodiment 4a kind of dextromethorphan hydrobromide oral cavity disperses membrane
Prescription is in table 21 and 22.
Preparation as follows:
1. get 250ml water, add the polacrilin potassium of recipe quantity, stir 1 hour;
2. in the good solution of above-mentioned suspendible, add the dextromethorphan hydrobromide of 12.5ml ethanol and 3.75g, stirring at room temperature, reacts 12 hours; Sucking filtration, discards filtrate, retains filter cake;
3. the dextromethorphan hydrobromide of 3.75g is dissolved in 250ml purified water to stirring and dissolving; After dextromethorphan hydrobromide dissolves completely, add above-mentioned filter cake to react, stirring at room temperature, reacts 10 hours.Sucking filtration, discards filtrate, retains filter cake; Filter cake cleans resin with the ethanol of 62.5ml;
4.～8. identical with step 5～9 of embodiment 1.
9. after above-mentioned adjuvant dissolves completely, stirring and dissolving 6.5g hypromellose E3;
10.～15. is identical with step 11～16 of embodiment 1.
embodiment 5a kind of dextromethorphan hydrobromide oral cavity disperses membrane
Prescription is in table 21 and 22.
Preparation by the following method:
1. the sodium hydroxide solution of the 1mol/L of 25ml is diluted to 200ml by purified water, and to be mixed evenly after, add the polacrilin of recipe quantity, the weight/mol ratio of polacrilin and sodium hydroxide is 1g:0.0025mol, stirs 6 hours;
2. in the good solution of above-mentioned suspendible, add the dextromethorphan hydrobromide of 10ml ethanol and 4g, stirring at room temperature, reacts 12 hours; Sucking filtration, discards filtrate, retains filter cake;
3. the dextromethorphan hydrobromide of 4g is dissolved in 200ml purified water to stirring and dissolving.After dextromethorphan hydrobromide dissolves completely, add above-mentioned filter cake to react, stirring at room temperature, reacts 10 hours; Sucking filtration, discards filtrate, retains filter cake;
～8. with 5. in embodiment 1～9. identical
9. get 160ml purified water, successively the propylene glycol of stirring and dissolving recipe quantity, cetomacrogol 1000, sorbitol, sucralose, essence;
10. after above-mentioned adjuvant dissolves completely, add successively dextromethorphan hydrobromide complex, the microcrystalline Cellulose of recipe quantity, dispersed with stirring is even;
Then 11. add coating powder, hypromellose E3, the hypromellose E50 of recipe quantity, stirring and dissolving successively;
12. evacuation leave standstill, until obviously bubble of nothing in visual observations solution;
13. coatings;
14. cuttings;
15. inner packings.
embodiment 6a kind of dextromethorphan hydrobromide oral cavity disperses membrane
Prescription is in table 21 and table 22.
Preparation by the following method:
1.～8. identical with the 1st～8th step in embodiment 1;
9. get 80ml purified water, the propylene glycol of stirring and dissolving recipe quantity, cetomacrogol 1000, hypromellose E3, hypromellose E50 successively, evacuation leaves standstill, and bubble removing, obtains solution A;
10. get 80ml purified water, stir successively the sucralose, essence, maltodextrin, coating powder, microcrystalline Cellulose, dextromethorphan hydrobromide complex, pregelatinized Starch, the low-substituted hydroxypropyl cellulose that add recipe quantity, dispersed with stirring is even, obtains solution B;
11. join solution B in solution A, stir;
12. evacuation leave standstill, until obviously bubble of nothing in visual observations solution;
13. coatings;
14. cuttings;
15. inner packings.
test example 1the dextromethorphan hydrobromide pelliculae pro cavo oris performance evaluating of embodiment 1～6 preparation
Outward appearance, mouthfeel, disintegration, dissolution time, the stability of the dextromethorphan hydrobromide pelliculae pro cavo oris to embodiment 1～6 preparation are investigated.The results are shown in Table 23.
Wherein the method for study on the stability is:
(1) strong illumination test: get this product, remove outer package, peek sheet, is loaded in plate, be placed in immediately under the illumination that light intensity is 4500lx ± 500lx and carry out strong illumination test, temperature is room temperature (25 DEG C), respectively at 0, sampling in 5,10 days, detects.
(2) hot test: get this product, remove outer package, peek sheet, is loaded in plate, is placed in 60 DEG C of calorstats and tests, and respectively at 0,5, sampling in 10 days, detects.
(3) high wet test: get this product, remove outer package, peek sheet, is loaded in plate, is placed in constant humidity container (relative humidity 75%) and places, tests under room temperature, and in 0,5, sampling in 10 days, detects.
Table 21 dextromethorphan hydrobromide complex prescription
Table 22 dextromethorphan hydrobromide oral cavity disperses membrane prescription
*: by dextromethorphan hydrobromide
Table 23 dextromethorphan hydrobromide pelliculae pro cavo oris the performance test results
a: temperature 60 C;
b: humidity 75%RH
Result shows dextromethorphan hydrobromide pelliculae pro cavo oris prepared by above-described embodiment, good mouthfeel, and also all stable under high temperature, high humidity and illumination condition.In addition, in preparation process, add if hypromellose E3 is disposable, can cause diaphragm to have " scratch ", although affect outward appearance, quality is not had to adverse effect.
test example 2dextromethorphan hydrobromide of the present invention oral cavity disperses membrane accelerated stability to investigate
According to formula and method described in embodiment 1, to prepare 3 batches of dextromethorphan hydrobromide oral cavities shown in table 24 and disperse membrane, specification is every and contains dextromethorphan hydrobromide 7.5mg.
Test agent in table 243 batch
| Lot number | 130401 | 130402 | 130403 |
| In batches | 40000 | 40000 | 40000 |
2.1 test method
Get the sample of this product simulation listing packaging, be placed in temperature and be 40 DEG C ± 2 DEG C, the calorstat of relative humidity 75% ± 5%, respectively at 1,2,3, sampling in June, investigate the indices of sample, comprise character, water activity, related substance, dissolution, assay and microbial check.The results are shown in Table 25 and 26.
2.2 investigate result
Table 25 limit test of microbe result
| Lot number | 130401 | 130402 | 130403 |
| 0 month | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| Accelerate June | Conform with the regulations | Conform with the regulations | Conform with the regulations |
Table 26 accelerates to keep sample measurement result
2.3 conclusion
The sample of three batches of simulation listing packagings, under the accelerated test condition of 40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%, places 6 months, and related substance slightly increases, and all the other every investigation indexs, without significant change, illustrate that described oral cavity disperses membrane stable in properties.
In a word, described dextromethorphan hydrobromide provided by the invention oral cavity disperses membrane and preparation method thereof, has solved well the problem of the bad mouthfeel of dextromethorphan hydrobromide, is especially applicable to child, old man patient, can significantly improve patient's compliance.By preferred preparation method, make oral cavity diaphragm more attractive in appearance.
Specific description of embodiments of the present invention above does not limit the present invention, and those skilled in the art can make according to the present invention various changes or distortion, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (14)
1. dextromethorphan hydrobromide oral cavity disperses a membrane, comprises dextromethorphan hydrobromide, film former, plasticizer, disintegrating agent, wetting agent, correctives, coloring agent and water; It is characterized in that, also comprise polacrilin or the polacrilin potassium of particle diameter at 50～150 μ m, dextromethorphan hydrobromide and polacrilin or polacrilin potassium form dextromethorphan hydrobromide complex, and the weight ratio of dextromethorphan hydrobromide and polacrilin or polacrilin potassium is 1:1～1:2; Described dextromethorphan hydrobromide complex is prepared by the following method:
(1) be 1:1～1:2 according to the part by weight of polacrilin or polacrilin potassium and dextromethorphan hydrobromide, prepare raw material; Dextromethorphan hydrobromide is divided into 2～4 parts;
(2) preparation sodium hydroxide solution, wherein liquor capacity is the more than 50 times of every part of dextromethorphan hydrobromide weight, polacrilin and sodium hydroxide weight/mol ratio are 1g:0.0025mol～1g:0.005mol; Polacrilin is added in described sodium hydroxide solution, stir 2～10 hours, obtain suspension; Or
Polacrilin potassium is added to the water, and the volume of water is the more than 50 times of every part of dextromethorphan hydrobromide weight, stirs 1～2 hour, obtains suspension;
(3) to the ethanol and the 1 part of dextromethorphan hydrobromide that add the volume 5% of described sodium hydroxide solution or water in above-mentioned suspension, under room temperature, stir 6～12 hours; Filter, discard filtrate, retain filter cake;
(4) separately get 1 part of dextromethorphan hydrobromide water-soluble, the volume of water is the more than 50 times of dextromethorphan hydrobromide weight, and the filter cake that adds previous step to obtain stirs 6～12 hours, filters, and retains filter cake;
(5) repeating step 4 operates, until that all dextromethorphan hydrobromides all react is complete, with ethanol or ethanol and water wheels stream washing leaching cake, 50 DEG C～70 DEG C dry, pulverize 80 mesh sieves.
2. dextromethorphan hydrobromide according to claim 1 oral cavity disperses membrane, it is characterized in that, the weight ratio of dextromethorphan hydrobromide and polacrilin or polacrilin potassium is 1:1.3～1:1.5.
3. dextromethorphan hydrobromide according to claim 1 and 2 oral cavity disperses membrane, it is characterized in that, comprises the raw material of following weight portion:
In 5～10 parts of the described dextromethorphan hydrobromide complex of dextromethorphan hydrobromide, film former 14-28 part, plasticizer 6-10 part, disintegrating agent 4-14 part, wetting agent 1-2 part, coloring agent 2～4 weight portions, correctives 1～3 weight portion, water 140-180 part;
Wherein, film former comprises hydroxypropyl methylcellulose;
Plasticizer comprises cetomacrogol 1000 and propylene glycol;
Disintegrating agent comprises microcrystalline Cellulose; ;
Wetting agent is selected from sorbitol and/or maltodextrin.
4. dextromethorphan hydrobromide according to claim 3 oral cavity disperses membrane, it is characterized in that, described film former also comprises pregelatinized Starch.
5. dextromethorphan hydrobromide according to claim 3 oral cavity disperses membrane, it is characterized in that, described plasticizer also comprises pregelatinized Starch.
6. dextromethorphan hydrobromide according to claim 3 oral cavity disperses membrane, it is characterized in that, disintegrating agent also comprises low-substituted hydroxypropyl cellulose.
7. according to claim, dextromethorphan hydrobromide oral cavity described in 3 disperses membrane, it is characterized in that, described film former is made up of hydroxypropyl methylcellulose E3 and hydroxypropyl methylcellulose E50, and weight ratio is hydroxypropyl methylcellulose E3: hydroxypropyl methylcellulose E50=5～7:1;
Described plasticizer is made up of cetomacrogol 1000 and propylene glycol, and weight ratio is cetomacrogol 1000: propylene glycol=2:1～3:1;
Described disintegrating agent is microcrystalline Cellulose;
Described wetting agent is sorbitol.
8. dextromethorphan hydrobromide according to claim 3 oral cavity disperses membrane, it is characterized in that, described coloring agent is selected from coating powder; Described correctives is selected from sucralose and/or essence.
9. disperse membrane according to arbitrary described dextromethorphan hydrobromide oral cavity in claim 4 to 7, it is characterized in that, described coloring agent is selected from coating powder; Described correctives is selected from sucralose and/or essence.
10. dextromethorphan hydrobromide according to claim 1 and 2 oral cavity disperses membrane, it is characterized in that, according to weight portion meter, raw material comprises:
11. dextromethorphan hydrobromide according to claim 1 and 2 oral cavities disperse membrane, it is characterized in that, according to weight portion meter, raw material comprises:
Dextromethorphan hydrobromide oral cavity in 12. claim 1 to 11 described in any one disperses the preparation method of membrane, comprises according to weight portion and gets each raw material, and be added to the water, dispersed with stirring is even, leaves standstill coating, cutting; Or
Get each raw material according to weight portion, described film former and plasticizer add in 1/2nd weight parts waters, are stirred to dissolve, and obtain solution A; Described dextromethorphan hydrobromide complex and remaining other adjuvant add in remaining water, and dispersed with stirring is even, obtains solution B; , mix with solution B during without bubble until solution A, stir, leave standstill, coating, cutting, to obtain final product.
Dextromethorphan hydrobromide oral cavity in 13. claim 7 to 11 described in any one disperses the preparation method of membrane, it is characterized in that, hydroxypropyl methylcellulose E3 gradation is added to the water.
Dextromethorphan hydrobromide oral cavity described in 14. claim 10 or 11 disperses the preparation method of membrane, it is characterized in that, specifically comprises the steps:
I. get each raw material according to weight portion, described dextromethorphan hydrobromide complex is crossed 80 mesh sieves;
II. under stirring, propylene glycol, cetomacrogol 1000, sorbitol, sucralose, essence are added to the water, make to dissolve;
III. under stirring, add 1/4th to 1/3rd hypromellose E3, make to dissolve;
IV. under stirring, add microcrystalline Cellulose and described dextromethorphan hydrobromide complex, make to be uniformly dispersed;
V. under stirring, add coating powder, hypromellose E50 and remaining hypromellose E3, make to dissolve;
VI. evacuation leaves standstill, until obviously bubble of nothing in visual observations solution;
VII. coating, film thickness is 110 μ m～130 μ m;
VIII. cutting;
IX. inner packing.
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Address after: 048000 Jincheng Development Zone, Jincheng, Shanxi Patentee after: Shanxi Royal Prime Minister's palace pharmaceutical Limited by Share Ltd Address before: 048000 Jincheng economic and Technological Development Zone, Shanxi Patentee before: Shanxi HCXF Pharmaceutical Co., Ltd. |