CN108785285A - The method that hot-melt extruded prepares dextrorotation oxiracetam oral quick-dissolving film preparation - Google Patents
The method that hot-melt extruded prepares dextrorotation oxiracetam oral quick-dissolving film preparation Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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Abstract
The present invention provides a kind of method that hot melt extruded prepares dextrorotation oxiracetam oral quick-dissolving film preparation, after mixing by the raw material including dextrorotation oxiracetam, filmogen, plasticizer and filler, it is added in hot melt film laminator, feed zone by heating film laminator is sent to hot melt area, raw material gradually melts mixing, the mixture of fusing continues through the output of dosage area, pours into mold, film is formed after cooling;Dextrorotation oxiracetam oral quick-dissolving film preparation thickness produced by the present invention is moderate, satisfactory mechanical property and disintegration time are shorter.Preparation method of the present invention is simple, is suitble to industrialized production.
Description
Technical field
The present invention relates to the preparation methods of dextrorotation oxiracetam oral quick-dissolving film preparation, and in particular to hot-melt extruded prepares right
Revolve the method for oxiracetam oral quick-dissolving film preparation.
Background technology
Oxiracetam (Oxiracetam), the entitled Esomeprazole of chemistry are big by anticipating
The cereboactive drug that sharp SmithKline ratio Qie Mu companies synthesized for the first time in 1974 is a kind of hydroxy-amino-butyric acid (GABOB) derivative, can promote
Into study, enhances memory, protect the medicine for central nervous system of damaged nerve cell.CN102552125A discloses its improvement
The mnemonic learning function of memory and amentia patient;It is also applied for light moderate vascular dementia, senile dementia and brain trauma etc.
Memory is with amentia or as its auxiliary therapy drug caused by disease.Studies have shown that d-isomer (the dextrorotation hydroxyl of oxiracetam
Oxygen pyrrole vinegar amine) in treatment cognition dysfunction, curative effect is poor in terms of improving learning memory;But the pharmacology with anti-epileptic is lived
Property, the effect for especially treating epilepsy generalized seizures, epilepsy partial seizures and status epilepticus is apparent.
CN101766596A discloses a kind of dextrorotation oxiracetam solid pharmaceutical preparation, including conventional tablet, oral disnitegration tablet, capsule,
Granule etc..These preparations dissolve out under one's belt mostly, and with the extension of residence time in stomach, dextrorotation oxiracetam is by hydrochloric acid in gastric juice
It destroys and increases, not only reduce curative effect of medication, also add side effect.Suffer from simultaneously for epilepsy (especially epileptic episodes)
For person, usually for drug dysphagia, dextrorotation oxiracetam capsule is taken, conventional tablet is inconvenient.Oral cavity speed
Molten film is a kind of in recent years in the oral administration solid quick-release novel form of external increasingly extensive application, since it has without drinking-water,
It can be made to have a variety of advantages in the unique distinction that oral cavity is dissolved rapidly, be particularly suitable for the patient of dysphagia.Although
Oral quick-dissolving film preparation has many advantages, but its filmogen and the limitation of preparation technique and cause drugloading rate low, disintegration time
Intensity is found with anti-tensile to be difficult to control, and constrains the development and application of oral quick-dissolving film preparation.
Invention content
The purpose of the present invention is to provide a kind of preparation method of dextrorotation oxiracetam oral quick-dissolving film preparation, this method with
The mode of hot-melt extruded is made dextrorotation oxiracetam oral quick-dissolving film preparation, and the film of preparation is not easy to spue after adhering on tongue,
It is suitble to the patient of dysphagia, and by mucosal absorption, avoids head and cross elimination effect, improve bioavilability.
Unless otherwise specified, number of the present invention is parts by weight;The percentage is mass percent.
Inventor has found in R&D process, and dextrorotation oxiracetam oral quick-dissolving film preparation is prepared using hot-melt extruded, at
The selection of membrane material prepares most important, the inappropriate dextrorotation oxiracetam mouth that will appear preparation of selection for the successful of film
The instant film intensity of chamber and/or toughness are bad, be easily broken off or prolonged disintegration, solution time are longer, are unfavorable for the suction of drug
The problems such as receipts.
The object of the present invention is achieved like this:
A kind of preparation method of dextrorotation oxiracetam oral quick-dissolving film preparation, which is characterized in that include the following steps:It will packet
Include the raw material including 25-55 parts of dextrorotation oxiracetams, 30-60 parts of filmogens, 5-15 parts of plasticizer and 5-30 parts of fillers
After mixing, it is added in hot melt film laminator, the feed zone by heating film laminator is sent to hot melt area, and gradually fusing is mixed for raw material
Even, the mixture of fusing continues through the output of dosage area, pours into mold, film is formed after cooling;The filmogen is propylene
The mixture of acid esters and pulullan polysaccharide, wherein acrylate are 1 with pulullan polysaccharide mass ratio:1~5;The plasticizer is selected
It is combined from one or more of propylene glycol, glycerine, triethyl citrate, glyceryl triacetate;The filler is selected from sweet dew
One or more of alcohol, low-substituted hydroxypropyl cellulose, pregelatinized starch, croscarmellose sodium combine.
An embodiment according to the present invention, raw material of the present invention further include 0.5-2 parts of corrigent, the corrigent choosing
It is combined from one or more of xylitol, Aspartame, sucrose, glucose, saccharin, fructose.
To further enhance the intensity and toughness of dextrorotation oxiracetam oral quick-dissolving film preparation prepared by the present invention, shortening is collapsed
The time limit is solved, filmogen of the present invention is acrylate and pulullan polysaccharide according to mass ratio 1:2~4.
In order to improve the demolding performace of the present invention, plasticizer preferably citric acid triethyl or/and triacetic acid glycerine of the present invention
Ester;Plasticizer and the dosage mass ratio of membrane material are 1: 6~1: 4.
To further increase the mechanical performance of the present invention, while improving dextrorotation oxiracetam oral quick-dissolving film preparation of the present invention
Appearance, the preferred low-substituted hydroxypropyl cellulose of the present invention or/and pregelatinized starch;Filler is with plasticizer consumption mass ratio
1: 1~2: 1.
In order to further enhance the mechanical performance of dextrorotation oxiracetam oral quick-dissolving film preparation prepared by the present invention, above-mentioned heat
The temperature in melting zone is 70-98 DEG C.
Disintegration time and patient adaptability in order to balance, dextrorotation oxiracetam oral quick-dissolving film preparation prepared by the present invention
Preferably 100~110 μm of thickness.
Specifically, the preparation method of dextrorotation oxiracetam oral quick-dissolving film preparation of the present invention, which is characterized in that including with
Lower step:To include 25-55 parts of dextrorotation oxiracetams, 30-60 parts of filmogens, 5-15 parts of plasticizer and 5-30 parts of fillers
Raw material inside after mixing, is added in hot melt film laminator, and the feed zone by heating film laminator is sent to hot melt area, control
The temperature for heating area is 70-98 DEG C, and raw material gradually melts mixing, and the mixture of fusing continues through the output of dosage area, pours into mould
Tool forms film after cooling;The filmogen is acrylate and pulullan polysaccharide according to mass ratio 1:2~4 mixture;
The plasticizer be triethyl citrate or/and glyceryl triacetate, wherein the dosage mass ratio of plasticizer and membrane material be 1: 6~
1:4;The filler is selected from low-substituted hydroxypropyl cellulose or/and pregelatinized starch, wherein filler and plasticizer consumption matter
Amount is than being 1: 1~2: 1.
Advantageous effect:
The present invention provides a kind of method that hot-melt extruded prepares dextrorotation oxiracetam oral quick-dissolving film preparation, the dextrorotation of preparation
Oxiracetam oral quick-dissolving film preparation is not easy to spue after adhering on tongue, is suitble to the patient of dysphagia, and is inhaled by mucous membrane
It receives, avoids head and cross elimination effect, improve bioavilability, reduce pharmaceutical dosage, to reduce drug side-effect.This
Invention mixes shape with acrylate to take into account filming performance, appearance and the disintegration time of oral quick-dissolving film preparation with pulullan polysaccharide
At compound film material, be made oral quick-dissolving film preparation through hot-melt extruded with the auxiliary materials such as plasticizer, filler, thickness is moderate, mechanicalness
Energy is good and disintegration time is shorter.Dextrorotation oxiracetam oral quick-dissolving film preparation appearance uniform prepared by the present invention is complete, color and luster
Uniformly, thickness is consistent, and physics and chemical property are stablized, and can dissolve with a small amount of saliva in oral cavity, is not required to use water delivery service
Medication, medication are convenient.The participation for not having water or organic solvent in preparation process of the present invention, avoiding causes since solvent exists
Air bubble problem and film in the high problem of moisture, be effectively guaranteed the equal of dextrorotation oxiracetam oral quick-dissolving film preparation
One property.The present invention is combined with specific filmogen with the plasticizer of particular types and dosage, to effective solution film
It is easily broken off, intensity and toughness is bad and prolonged disintegration, solution time is longer, is unfavorable for the technical problems such as the absorption of drug, real
Having showed keeps dextrorotation oxiracetam oral quick-dissolving film preparation demolding performace obtained good, and medicine film is soft, and not with fracture, fusing time is short
Excellent results.Preparation method of the present invention is simple, is suitble to industrialized production.
Embodiment
In order to keep the purpose of the present invention and technical solution clearer, the preferred embodiment of the present invention is carried out below detailed
Description.To illustrate that:Following embodiment is served only for that the present invention is further detailed, and should not be understood as to this hair
The limitation of bright protection domain.It is commercial product that the present invention, which heats film laminator, as the GMP hot melts of Shanghai Zhou Xing Industrial Co., Ltd.s squeeze
Go out film laminator etc., hot melt press mold technique can refer to following documents and carry out:Repka MA,Battu SK,Upadhye SB,et
al.Pharmaceutical applications of hot-melt extrusion:part II[J].Drug Dev Ind
Pharm,2007,33(10):Raw material mixed charging rate when 1043-1057. hot melt extrudeds of the present invention, mold, output speed
Degree is selected or is adjusted according to actual needs by those skilled in the art.The raw materials used in the present invention and reagent are commercial product,
(content 99.8%, Chongqing Dongze Pharmaceutical Technology Development Co., Ltd. provide middle dextrorotation oxiracetam raw material, and lot number is:
20161002);Acrylate (Eudragit, Dow Chemical company, model E);Polyoxyethylene (PEO, Dow Chemical
Company, specification N10);Pulullan polysaccharide (the Shandong bio tech ltd Fu Ruida);(Hunan that health pharmacy share has glycerine
Limit company);Propylene glycol (Dongying City grand Xinghua work Co., Ltd);Triethyl citrate (TEC, the rich former medical sci-tech in Bangbu
Development Co., Ltd);Glyceryl triacetate (Aladdin Reagent Company);Low-substituted hydroxypropyl cellulose (L-HPC), pregelatinated form sediment
Powder (Anhui Shanhe Medicinal Subsidiary Material Co., Ltd.);Mannitol (French Roquette companies);Pectin (Zhengzhou Xin Tianyuan chemical industry
Co., Ltd, methoxyl content >=7%).
Preparation process
Dextrorotation oxiracetam, filmogen, filler, plasticizer, cosolvent and corrigent are mixed, are uniformly mixed
Afterwards, it being sent to hot melt area by heating the feed zone of film laminator, the mixture of fusing continues through the output of dosage area, pours into mold,
Film is formed after cooling.
Performance test
Dextrorotation oxiracetam orodispersible film obtained is evaluated, including thickness, ifs vitro disintegration, mechanical performance
Etc. evaluation.N is the dextrorotation oxiracetam oral quick-dissolving film preparation piece number measured.
Assay method
Thickness and quality:With calibrator thickness measurement (4 angles and center), and accurate title are carried out in the different position of film
Fixed every piece of film quality, calculates mean value and standard deviation.
Mechanical performance:Weighing film mechanical performance mainly has 3 indexs:Tensile strength, elongation and folding strength.By film
2.0cm × 3.0cm sizes are cut into, every piece of film uses tensile testing machine (tensile speed 25mm/min) longitudinal stretching, directly
Until film is broken, record reading calculates tensile strength and elongation.The same position of film it is folding to its fracture with
The folding strength for measuring film, folding strength is indicated with the logarithm of twofold number before fracture.
Disintegration time:Film is put into the beaker equipped with 37 DEG C of purified water 50ml, is vortexed.It visually observes, records film
The disintegration time, at least take 3 pieces of films to be measured.
Embodiment 1
By 39 parts of dextrorotation oxiracetams, 8 parts of acrylate, 32 parts of pulullan polysaccharides, 10 parts of glyceryl triacetates, 10 parts
Pregelatinized starch, 1 part of fructose mixing, after mixing, the feed zone by heating film laminator is sent to hot melt area, at 81-83 DEG C
The mixture of hot melt, fusing continues through the output of dosage area, pours into mold, film is formed after cooling.
Embodiment 2
By 25 parts of dextrorotation oxiracetams, 18 parts of acrylate, 36 parts of pulullan polysaccharides, 10 parts of glyceryl triacetates, 10
Part low-substituted hydroxypropyl cellulose, 1 part of xylitol mixing, after mixing, the feed zone by heating film laminator is sent to hot melt
Area is heated at 70-72 DEG C, and the mixture of fusing continues through the output of dosage area, pours into mold, film is formed after cooling.
Embodiment 3
By 55 parts of dextrorotation oxiracetams, 10 parts of acrylate, 20 parts of pulullan polysaccharides, 7 parts of triethyl citrates, 7 parts
Low-substituted hydroxypropyl cellulose, 1 part of Aspartame mixing, after mixing, the feed zone by heating film laminator is sent to hot melt
Area is heated at 95-98 DEG C, and the mixture of fusing continues through the output of dosage area, pours into mold, film is formed after cooling.
The thickness of thickness dextrorotation oxiracetam pelliculae pro cavo oris prepared by embodiment 1-3, elongation, tensile strength, disintegration
Time etc. measures with reference to the above method, and measurement result see the table below 1.
The performance measurement result of 1 dextrorotation oxiracetam pelliculae pro cavo oris of table
Note:1)The n=10 of the n=6 of thickness, quality and mechanical performance, content and uniformity of dosage units
By the testing result of embodiment 1-3 in table 1 it is found that gained film thickness evenness is preferable, have suitable flexible
Degree and tensile property, Mean disintegration time are no more than 25s.
Dextrorotation oxiracetam orodispersible film made from above-described embodiment 1-3 is subjected to dissolution in vitro experiment, it is molten
Out-degree, which measures, uses slurry processes, measures the dissolution rate of the dextrorotation oxiracetam orodispersible film of embodiment, and dissolution medium is water,
Dissolution volume is 1000mL, and temperature is 37 DEG C, rotating speed 100rpm.As a result it shows:The dextrorotation oxiracetam oral cavity of embodiment 1-3
Disperse film to start to be disintegrated in 10s, drug release is rapid, and the interior dissolutions of 5min dissolve out completely substantially more than 80%, 10min.
Investigate influence of the membrane material to film property
With reference to the preparation method of embodiment 1, with 32 parts of dextrorotation oxiracetams, 47 parts of filmogens, 10 parts of plasticizer (three
Acetin), 10 parts of fillers (pregelatinized starch) and 1 part of corrigent (Aspartame) be that raw material prepares dextrorotation hydroxyl oxygen pyrrole vinegar
Amine orodispersible film.Choose acrylate (Eudragit), pulullan polysaccharide, polyoxyethylene, the polymer such as chitosan be at
Membrane material, and using thickness, elongation, tensile strength and disintegration time as evaluation index, investigate influence of the membrane material to film property.
Eudragit in embodiment: pulullan polysaccharide is mass ratio, such as Eudragit: pulullan polysaccharide (1:1) it is Eudragit: Pu Lu
Blue polysaccharide mass ratio 1:1;Similarly hereinafter.It the results are shown in Table 2.
2 membrane material of table to film property influence (N=6)
As shown in Table 2, using acrylate: the compound film material that pulullan polysaccharide is formed is relative to using chitosan, polyoxy
The dextrorotation oxiracetam orodispersible film that ethylene, acrylate or pulullan polysaccharide are prepared through hot melt extruded has more
Good mechanical performance and shorter disintegration time, dextrorotation oxiracetam orodispersible film prepared by embodiment 8-12 averagely collapse
The time is solved less than 25s, is very suitable for Clinical practice.
Dextrorotation oxiracetam orodispersible film made from above-described embodiment 8-12 is subjected to dissolution in vitro experiment, it is molten
Out-degree, which measures, uses slurry processes, measures the dissolution rate of the dextrorotation oxiracetam orodispersible film of embodiment, and dissolution medium is water,
Dissolution volume is 1000mL, and temperature is 37 DEG C, rotating speed 100rpm.As a result it shows:The dextrorotation oxiracetam mouth of embodiment 8-12
Chamber disperses film and starts to be disintegrated in 10s, and drug release is rapid, and the interior dissolutions of 5min dissolve out completely substantially more than 80%, 10min.Increase
Agent type is moulded to investigate with dosage
Plasticizer is an important factor for influencing film mechanical performance, and dosage can also influence film performance.With reference to embodiment 1
Preparation method, with 34 parts of dextrorotation oxiracetams, 45 parts of filmogens (acrylate EudragitE, pulullan polysaccharide quality
Than 1:4), 10 parts of plasticizer, 10 parts of fillers (pregelatinized starch) and 1 part of corrigent (xylitol) are that raw material prepares dextrorotation hydroxyl oxygen
Pyrrole vinegar amine orodispersible film.Plasticizer is chosen in this experiment:Propylene glycol, glycerine, triethyl citrate, glyceryl triacetate, with
Tensile strength and disintegration time are evaluation index, investigate its influence to film property.The result shows that with glycerine and propylene glycol system
Standby film is easily mutually adhered, and matter is soft, therefore selects glyceryl triacetate or triethyl citrate for film plasticizer.As a result it shows
Show, when glyceryl triacetate and membrane material ratio are less than 1: 12, the demoulding of film is poor;With the increasing of glyceryl triacetate dosage
Add, the tensile strength of film also gradually increases, and disintegration time is in increase trend.To take into account film tensile strength and fater disintegration
Characteristic, it is final to determine that the amount ratio of glyceryl triacetate and membrane material is 1: 6~1: 4.
Filler type and dosage are investigated
Filler can improve the dispersibility of film appearance and dextrorotation oxiracetam orodispersible film, to film mechanicalness
Can also there be certain influence.With reference to the preparation method of embodiment 1, with 30 parts of dextrorotation oxiracetams, 48 parts of filmogen (acrylic acid
Ester EudragitE, pulullan polysaccharide mass ratio 1:2), 10 parts of plasticizer (glyceryl triacetate), 10 parts of fillers and 1 part of flavoring
Agent (Aspartame) is that raw material prepares dextrorotation oxiracetam orodispersible film.This experiment is with mannitol, low substituted hydroxy-propyl
Cellulose, pregelatinized starch, croscarmellose sodium are filler, investigate it to film appearance, thickness and disintegration time
Influence.The result shows that making the film of filler preparation with mannitol, irregular crystal is precipitated in drying process, leads to film
Appearance uniform degree is poor;Sand type is apparent when using croscarmellose sodium as filler, uneven thickness;Using low-substituted hydroxypropyl
The products appearance even uniform of base cellulose, and dextrorotation oxiracetam fine dispersion can be made;Pregelatinized starch can then reduce film
Agent makes film faster disintegration in mouth to the adhesion of tooth and palate.The results show that filler loading is excessive, i.e. solid content
Increase, causes film partially thick, and film easily crimps, flatness is bad, and disintegration time also slows down;Consider from patient using angle,
Film thickness should not be too thin, therefore finally determines that filler and plasticizer consumption ratio are 1: 1~2: 1.
Claims (10)
1. a kind of preparation method of dextrorotation oxiracetam oral quick-dissolving film preparation, which is characterized in that include the following steps:To include
Raw material including 25-55 parts of dextrorotation oxiracetams, 30-60 parts of filmogens, 5-15 parts of plasticizer and 5-30 parts of fillers is mixed
It after closing uniformly, is added in hot melt film laminator, the feed zone by heating film laminator is sent to hot melt area, and gradually fusing is mixed for raw material
Even, the mixture of fusing continues through the output of dosage area, pours into mold, film is formed after cooling;The filmogen is propylene
The mixture of acid esters and pulullan polysaccharide, wherein acrylate are 1 with pulullan polysaccharide mass ratio:1~5;The plasticizer is selected
It is combined from one or more of propylene glycol, glycerine, triethyl citrate, glyceryl triacetate;The filler is selected from sweet dew
One or more of alcohol, low-substituted hydroxypropyl cellulose, pregelatinized starch, croscarmellose sodium combine.
2. method as described in claim 1, it is characterised in that:The raw material further includes 0.5-2 parts of corrigent, the corrigent
It is combined selected from one or more of xylitol, Aspartame, sucrose, glucose, saccharin, fructose.
3. method as claimed in claim 1 or 2, it is characterised in that:The filmogen is that acrylate is pressed with pulullan polysaccharide
According to mass ratio 1:2~4.
4. method as claimed in claim 1 or 2, it is characterised in that:The plasticizer is that triethyl citrate or/and triacetic acid are sweet
Grease;The dosage mass ratio of the plasticizer and membrane material is 1: 6~1: 4.
5. method as claimed in claim 3, it is characterised in that:The plasticizer is triethyl citrate or/and triacetic acid glycerine
Ester;The dosage mass ratio of the plasticizer and membrane material is 1: 6~1: 4.
6. such as claim 1,2 or 5 the methods, it is characterised in that:The filler be low-substituted hydroxypropyl cellulose or/and
Pregelatinized starch;The filler is 1: 1~2: 1 with plasticizer consumption mass ratio.
7. method as claimed in claim 4, it is characterised in that:The filler is low substitution pulullan polysaccharide or/and pregelatinated
Starch;The filler is 1: 1~2: 1 with plasticizer consumption mass ratio.
8. method as described in claim 1, it is characterised in that:The temperature in the hot melt area is 70-98 DEG C.
9. such as any one of claim 1-8 the methods, it is characterised in that:The dextrorotation oxiracetam oral quick-dissolving film preparation
Thickness is 100~110 μm.
10. the preparation method of dextrorotation oxiracetam oral quick-dissolving film preparation, which is characterized in that include the following steps:To include 25-
Raw material mixing including 55 parts of dextrorotation oxiracetams, 30-60 parts of filmogens, 5-15 parts of plasticizer and 5-30 parts of fillers is equal
It after even, is added in hot melt film laminator, the feed zone by heating film laminator is sent to hot melt area, and the temperature in control hot melt area is
70-98 DEG C, raw material gradually melts mixing, and the mixture of fusing continues through the output of dosage area, pours into mold, formed after cooling
Film;The filmogen is acrylate and pulullan polysaccharide according to mass ratio 1:2~4 mixture;The plasticizer is
The dosage mass ratio of triethyl citrate or/and glyceryl triacetate, wherein plasticizer and membrane material is 1: 6~1: 4;The filling
Agent is selected from low-substituted hydroxypropyl cellulose or/and pregelatinized starch, and wherein filler and plasticizer consumption mass ratio are 1: 1~2:
1。
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US11648197B2 (en) | 2018-06-28 | 2023-05-16 | Arx, Llc | Dispensing method for producing dissolvable unit dose film constructs |
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