CN102908331A - Duloxetine hydrochloride enteric capsules and preparation method thereof - Google Patents
Duloxetine hydrochloride enteric capsules and preparation method thereof Download PDFInfo
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- CN102908331A CN102908331A CN201110220256XA CN201110220256A CN102908331A CN 102908331 A CN102908331 A CN 102908331A CN 201110220256X A CN201110220256X A CN 201110220256XA CN 201110220256 A CN201110220256 A CN 201110220256A CN 102908331 A CN102908331 A CN 102908331A
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Abstract
The invention relates to the technical field of medicinal preparations, in particular to duloxetine hydrochloride-containing enteric capsules and a preparation method thereof. The enteric capsules consist of capsule shells and coated pellets, wherein the coated pellets also comprise duloxetine hydrochloride-containing medicine carrying pellet cores and coating layers; and the medicine carrying pellet cores contain a disintegrating agent. In preparation of the medicine carrying pellet cores, the duloxetine hydrochloride raw material is subjected to super micronization, so that the particle size distribution that the diameter of 99 percent is not greater than 50 mum, the diameter of 90 percent is not greater than 35 mum, the diameter of 50 percent is not greater than 20 mum and the diameter of 5 percent is not greater than 10 mum is achieved; and after the disintegrating agent is added into the medicine carrying pellet cores, the release speed of the medicine in intestines is increased. According to the duloxetine hydrochloride-containing enteric capsules and the preparation method thereof, a method of directly preparing the medicine carrying pellet cores is adopted, so that the complexity for loading a medicine on blank pellets of the existing domestic and foreign similar products is reduced, the technological process is simplified, and the duloxetine hydrochloride raw material is firstly crushed to a certain particle size range and then prepared into the medicine carrying pellet cores; and the prepared capsules have uniform medicine content and high reproducibility and are suitable for industrial production.
Description
Technical field
The present invention relates to technical field of medicine, be specifically related to a kind of enteric coated capsule that contains duloxetine hydrochloride and preparation method thereof.
Background technology
Along with living standards of the people are more and more higher, operating pressure is also increasing, people's psychological endurance intensity is also suffering huge challenge, there is approximately 12% people suffer from depression according to bibliographical information, but the effective percentage of present clinically existing antidepressants is less than 70%, onset time is generally more than 15 days, and some side reactions that are difficult to tolerate (sexual dysfunction, serious gastrointestinal reaction) are arranged, so that a lot of patient has lost the confidence for the treatment of.And duloxetine is a kind of 5-hydroxy tryptamine and the dual reuptake inhibithors of norepinephrine (SNRI).As antidepressant safely and effectively in the antidepressant drug, can effectively treat major depressive disorder in the clinical research, its side effect is little, and safety is good, generally without xerostomia, hypotension, the untoward reaction such as excessively calm, to the cardiac conduction unrestraint etc.But the duloxetine raw material is liquid, is insoluble in water, thus often be made into various salts, more with hydrochlorate.
Duloxetine hydrochloride (Duloxetine hydrochloride), its chemical name is: S-(+)-N-methyl-3-(1-naphthyl oxygen base)-3-(2-thienyl)-propylamin hydrochloride, its structural formula is:
Duloxetine hydrochloride molecular formula: C
18H
19NOSHCl; C
18H
20ClNOS, molecular weight: 333.88, fusing point 118-122 ℃, more unstable to light for off-white color crystalline powder or powder, the dissolubility in water is relatively poor and unstable under sour environment, is easy to degraded.
Duloxetine hydrochloride is a kind of 5-hydroxy tryptamine and the norepinephrine double-absorption inhibitor by Lilly Co., Eli. (Eli lilly and company) exploitation, is a kind of safely and effectively antidepressant.It has following advantage: 1. act on two the crucial neurotransmitteies relevant with depression, improve somatization, such as whole body pain and gastrointestinal dysfunction.2. rapidly onset, the multiple symptom of alleviate depression disease comprises myalgia, abdominal colic and headache.3. effective to women's tonicity urinary incontinence.4. be used for the treatment of the patients with depression that produces owing to diabetes, obesity.
Duloxetine hydrochloride is off-white color crystalline powder or powder, to photo-labile, dissolubility in water is relatively poor and unstable under sour environment, be easy to degraded, in order to guarantee that medicine does not react with acidic materials, therefore it should be prepared into enteric coated preparation, need a kind of dissolubility that can increase medicine can guarantee again not enteric coated preparation that reacts with acid and preparation method thereof.What the present invention selected is the enteric solubility pellet capsule.(Eli Lilly company is produced in USA to the listing preparation according to the inventor, trade name glad hundred reaches, specification 60mg, 30mg) investigate, discharge detection method with reference to its import standard and the selected stripping of two appendix XC of Chinese Pharmacopoeia version in 2010 dissolution method: the basket method, rotating speed 75 turns, the aqueous hydrochloric acid solution that front 2 hours dissolution mediums are 0.1mol/l, rear 45 minutes is 6.8 buffer salt solution for pH value, the result shows that the listing preparation discharged all less than 10% in hydrochloric acid solution at front 2 hours, principal agent discharged rapidly in buffer salt in rear 45 minutes, discharged to reach more than 90%.
Through retrieval, European patent EP 0693282, US Patent No. 20070292511 all disclose the enteric coated capsule preparation of duloxetine, but both adopted the mode of fluid bed medicine-feeding commonly used, and the medicine-feeding layer of medicine-feeding all needs with alcoholic solution again medicine-feeding of duloxetine hydrochloride dissolving, the very big like this consumption that increases solvent has prolonged the medicine-feeding time, and medicine-feeding has increased difficulty to coating, because the coating time is longer, also require higher to the condition of coating.Discharge rapidly in intestinal juice in order to increase medicine, also increased the consumption of cosolvent.
The domestic patent No. is to disclose a kind of duloxetine pellet capsule and preparation method thereof in 200410067161.9 the patent application, but the medicine-feeding method in this patent, also be first principal agent, water-solubility carrier, diluent, antiplastering aid and antioxidant to be dissolved in the ethanol water, add medicine at blank piller again.Also having mentioned a kind of solid dispersion technology among the embodiment of this patent application, is the recipe quantity duloxetine to be added carrier be prepared into solid dispersion, pulverizes again, and the mode that adopts step coating granulator medicine-feeding mode solid commonly used to execute powder is added medicine to.Although this mode can be used, can cause medicine-feeding inhomogeneous, pellet size differs, and the response rate is lower, and repeatability is bad.
The common ground of above-mentioned patent all is to prepare first blank piller to add medicine to again, discharges rapidly although can reach like this in small intestinal, and blank piller drug layering parameter request is strict, and technique is loaded down with trivial details, and preparation time is long, and suitability for industrialized production is not easy control.
Summary of the invention
In order to solve the above-mentioned problems in the prior art, the invention provides a kind of duloxetine hydrochloride enteric coated capsule and preparation method thereof, this duloxetine hydrochloride enteric coated capsule medicament contg is even, favorable reproducibility, and preparation technology is simple, is fit to large-scale production.To achieve these goals, the invention provides following technical scheme:
A kind of duloxetine hydrochloride enteric coated-pellet is comprised of year pill core and the coatings that comprise duloxetine hydrochloride, contains disintegrating agent in the described year pill core.
Coated micropill of the present invention mainly is comprised of a year pill core, sealing coat, enteric layer, can also add complete layer.Sealing coat can increase the compactness of coating, and the reaction of coating in principal agent and the enteric coat layer increase micropill smoothness of the surface, compactness, light-proofness, and complete layer is so that micropill is more stable in the minimizing year pill core.
Medicine carrying ball core diameter size of the present invention is 0.425mm～1.4mm.
The chief component of of the present invention year pill core and quality proportioning are as follows:
5～40 parts of principal agents;
0.5～15 part of bonding agent;
30～80 parts of filleies;
1～10 part of disintegrating agent;
0～5 part of antiplastering aid;
0.01～5 part in surfactant.
Wherein principal agent is duloxetine hydrochloride, bonding agent is a kind of in sodium carboxymethyl cellulose, hypromellose (HPMC), polypyrrole alkane ketone (PVP), the hypromellose, filler is one or several the compositions in sucrose, microcrystalline Cellulose or the lactose etc., disintegrating agent is a kind of in carboxymethyl starch sodium, cross-linked pvp or the cross-linking sodium carboxymethyl cellulose, antiplastering aid is one or several the compositions in micropowder silica gel, the Pulvis Talci etc., and the surface activity preparation is a kind of in sodium lauryl sulphate, poloxamer or the POLYSORBATE 80.
The dissolubility of principal agent duloxetine hydrochloride in water and alcohol is not fine, and as insoluble drug, it discharges-absorbs with the dispersity relation of medicine very close, dispersity is very large to its release-inhalation effects, the powder of the loose state of the rough segmentation that makes with general breaking method, often because the dissolubility of principal agent is very low, can not reaches rapidly fully release at small intestinal, thereby reduce bioavailability.Poor in order to solve preferably the duloxetine dissolubility, better promote its emission and absorption in vivo, in the formulation and technology process, duloxetine hydrochloride is carried out high pressure draught and pulverize, it is ground into the particle size range that needs, greatly increased the dissolubility of medicine in buffer salt.After the pulverizing, the particle size range of duloxetine hydrochloride distributes and reaches: 99% diameter is not more than 50 μ m, and 90% diameter is not more than 35 μ m, and 50% diameter is not more than 20 μ m, and 5% diameter is not more than 10 μ m.And in order to discharge rapidly at enteral, added disintegrating agent in micropill, so that micropill discharges rapidly after the disintegrate in intestinal.
The mass percent of described disintegrating agent in carrying pill core is 1% to 10%.
Described bonding agent need add first solvent before using, and described solvent is ethanol, water or both mixture.The use amount of described solvent accounts for 0.5～10% of solvent according to bonding agent and carries out the quality proportioning.
The component of enteric layer of the present invention and quality proportioning are as follows:
70～100 parts of enteric materials;
0～15 part of plasticizer;
0～20 part of antiplastering aid;
0～10 part of opacifier.
Said components is solid constituent, also need to use solvent to make its dissolving or dispersion if finish the art for coating of enteric coating, owing to also be dry run in the time of coating, therefore the component of enteric layer is not described the composition of solvent, the use amount of solvent accounts for 5～30% of solvent according to the enteric material solid content and carries out the quality proportioning, and the quality proportioning of the use amount of solvent and other components of its enteric layer by that analogy.
Its effect of enteric layer of the present invention is so that medicine does not discharge substantially at stomach, reduces the stimulation to stomach, allows medicine discharge at sour environment and slowly or does not substantially discharge, and can discharge rapidly in intestinal juice.
Further, described enteric material is a kind of in cellulose acetate-phthalate, hydroxypropyl methyl acetic acid succinate, Hydroxypropyl Methylcellulose Phathalate, vinyl acetate phthalic acid ester, acrylic resin, the EUDRAGIT L100.Above-mentioned these polymer can be dry powder or aqueous dispersion, and the adjuvant that can obtain in market comprises the methacrylic acid copolymer with the sale of Eudragit (L100, S100, L30D-55) trade mark that Rohm drugmaker produces; The Cellacefate (cellulose acetate-phthalate) that Eastman chemical company produces; The Aqoat (hydroxypropyl methyl acetic acid succinate aqueous dispersion) that the Aquateric (cellulose acetate-phthalate aqueous dispersion) that FMC Corp. produces and Shin EtsuK.K produce.Plasticizer is selected dibutyl sebacate, diethyl phthalate or triethyl citrate.Opacifier is a kind of in titanium dioxide (titanium dioxide), iron oxide red, the iron oxide yellow, and the protection medicine avoids medicine to be directly exposed under the light, thereby improves the stability of preparation., solvent can be the mixed solution of a kind of in water or the ethanol or two kinds.Some company proportionally mixes more convenient client with each composition of these enteric materials and uses, the crylic acid resin enteric material pressed powder Acryl-EZE that colorcon company is arranged that can obtain in market, and methacrylic resin class pressed powder OPADRY ENTERIC etc.
Because the emptying time of stomach is about 2 hours, slowly discharged in 2 hours or substantially do not discharge at gastric juice in order to reach medicine, again owing to added disintegrating agent in this medicine carrying ball, thickness to enteric coating has proposed strict requirement, and the weightening finish of described enteric layer (according to the weightening finish of enteric material) is 10～40%., according to the difference of enteric material, weightening finish also can be different.
Described sealing coat refers to that the one deck that adds mainly plays the material of buffer action between year pill core and enteric coat layer, its component and quality proportioning are:
70～100 parts of water-soluable gel materials;
0～20 part of antiplastering aid;
0～10 part of plasticizer;
0～10 part of opacifier;
Finish the coating of sealing coat, also need to add corresponding solvent in above-mentioned solid constituent just can finish, the use amount of solvent accounts for 3～20% of solvent according to the water-soluable gel material and carries out the quality proportioning, and the quality proportioning of the use amount of solvent and other components of described sealing coat by that analogy.
The effect of sealing coat of the present invention is to provide a smooth surface to enteric layer, suppresses wherein enteric polymer and the interaction of carrying principal agent in the pill core, allows simultaneously enteric coating better adhere to up.
Further, in the component of described sealing coat, the water-soluable gel material is a kind of in hypromellose or the polyvinylpyrrolidone; Antiplastering aid comprises the mixture of a kind of in Pulvis Talci, the micropowder silica gel or two kinds; Plasticizer is Polyethylene Glycol; Opacifier is one or both the compositions in titanium dioxide, iron oxide red, the iron oxide yellow; Solvent can be the mixed solution of a kind of in water or the ethanol or two kinds.
For outward appearance and the stability of improving product, the present invention also can wrap one deck complete layer again outside enteric layer, and the component proportion of complete layer is identical with sealing coat.
A kind of duloxetine hydrochloride enteric coated capsule, described duloxetine hydrochloride enteric coated capsule is comprised of capsule shells and above-mentioned coated micropill, and wherein capsule shells is hard capsule case, usually mainly adds other adjuvants by pharmagel and forms.
A kind of preparation method of described duloxetine hydrochloride enteric coated-pellet is: the duloxetine hydrochloride raw material is carried out micronization processes, reaching particle size range is distributed as: 99% diameter is not more than 50 μ m, 90% diameter is not more than 35 μ m, 50% diameter is not more than 20 μ m, 5% diameter is not more than 10 μ m, according to the prescription proportioning of carrying pill core, the preparation particle size range is the pill core that carries of 0.425mm～1.4mm, according to each coatings formulation ratio, carry out coating with the fluid bed mode, prepare coated micropill.The coated micropill for preparing is carried out the encapsulating capsule namely get described duloxetine hydrochloride enteric coated capsule.
Further, capsule of the present invention can prepare according to following technique:
(1) first raw material is carried out micronization processes, particle size distribution is as follows: particle size range is: 99% diameter is not more than 50 μ m, and 90% diameter is not more than 35 μ m, and 50% diameter is not more than 20 μ m, and 5% diameter is not more than 10 μ m;
(2) adopt and to extrude method for rolling circle and carry pill core according to formula preparation, particle size range is 0.425mm～1.4mm;
(3) will carry pill core and prepare the sealing coat coating solution according to sealing coat prescription proportioning and aqueous solution or alcoholic solution, and adopt the usual manner fluid bed to carry out the sealing coat coating, weightening finish 1-10%.；
(4) with the micropill of the complete sealing coat of above-mentioned bag, according to enteric layer recipe quantity proportioning, adopt conventional fluid bed mode to carry out the enteric layer coating, weightening finish 10-40%, weightening finish is decided on concrete enteric material;
(5) also can at micropill described in (4) according to the complete layer proportioning of writing out a prescription, take conventional fluid bed mode to finish coating as required;
(6) coated micropill that will finish coating carries out the encapsulating capsule.
The present invention has carried out careful investigation to each embodiment stripping release profiles etc., shows that stripping of the present invention discharges to reach substantially not discharge in the acid flux material, discharges rapidly in pH value is 6.8 buffer salt.
The present invention adopts direct preparation to carry the mode of pill core, has simplified technical process.In the time of preparation ball core, in the ball core, added disintegrating agent, and strictly controlled the particle size distribution of raw material, can make and carry a pill core and in small intestinal, discharge rapidly and reach and the identical or better releasing effect of listing preparation.The present invention will be crushed to certain particle size range first, then be prepared into to carry pill core, not need to add solubilizing agent, and the pharmaceutical capsules content that makes is even, favorable reproducibility, and technique is simple, and easily operation is fit to large-scale production.Adopt the micropill of technique of the present invention substantially not discharge at stomach, discharge in the rapid disintegrate of enteral, and can reach identical with the listing preparation or better discharge and bioavailability.
The specific embodiment
In order further to understand the present invention, below in conjunction with embodiment duloxetine hydrochloride enteric coated capsule provided by the invention and preparation method thereof is elaborated.It will be appreciated that these embodiment describe just as further describing feature of the present invention, rather than to the restriction of the scope of the invention or claim scope of the present invention.
Embodiment 1
With the duloxetine hydrochloride comminution by gas stream, particle size distribution range is: 99% diameter is not more than 50 μ m, 90% diameter is not more than 35 μ m, and 50% diameter is not more than 20 μ m, and 5% diameter is not more than 10 μ m, for subsequent use, take by weighing recipe quantity duloxetine hydrochloride, sucrose, microcrystalline Cellulose, cross-linked pvp, sodium lauryl sulphate mix homogeneously by prescription 1,5% hypromellose aqueous solution is done binding agent, the preparation soft material, be prepared into the pill core that carries that diameter is 0.425mm～1.4mm with extruding spheronizator, for subsequent use.Sealing coat coating solution preparation: with the water of recipe quantity hypromellose adding recipe quantity, add again the Polyethylene Glycol stirring and make dissolving for subsequent use.Pulvis Talci, titanium dioxide are added, and restir is even, low rate mixing half an hour continues to stir lower, carries out coating with fluid bed.Enteric layer preparation: take by weighing recipe quantity EudragitL30D-55, triethyl citrate and add be uniformly dispersed rear adding recipe quantity Pulvis Talci, titanium dioxide of recipe quantity purified water and stir that making is uniformly dispersed carries out coating afterwards with fluid bed.Complete layer preparation: after taking by weighing recipe quantity hypromellose, Polyethylene Glycol adding recipe quantity purified water dissolve complete, add the dispersion that stirs of recipe quantity Pulvis Talci, iron oxide yellow, iron oxide red, the coating that fluid bed is finished respectively each layer makes coated micropill, again the encapsulating capsule.
Prescription 1
Embodiment 2
With the duloxetine hydrochloride comminution by gas stream, particle size distribution range is: 99% diameter is not more than 40 μ m, 90% diameter is not more than 25 μ m, and 50% diameter is not more than 10 μ m, and 5% diameter is not more than 5 μ m, for subsequent use, take by weighing recipe quantity duloxetine hydrochloride, carboxymethyl starch sodium, sucrose, starch, sodium lauryl sulphate mix homogeneously by prescription 2,5% hypromellose is done binding agent, the preparation soft material, be prepared into the pill core that carries that diameter is 0.425mm～1.4mm with extruding spheronizator, for subsequent use.Sealing coat coating solution preparation: recipe quantity ketopyrrolidine (PVP) is added the water of recipe quantity, for subsequent use after the stirring and dissolving, again Pulvis Talci, titanium dioxide are added, restir is even, low rate mixing half an hour continues to stir lower, carries out coating with fluid bed.Enteric layer preparation: take by weighing recipe quantity EudragitL30D-55, dibutyl sebacate and add be uniformly dispersed rear adding recipe quantity Pulvis Talci, titanium dioxide of recipe quantity purified water and stir that making is uniformly dispersed carries out coating afterwards with fluid bed, obtain coated micropill, again the encapsulating capsule.
Prescription 2
Embodiment 3
With the duloxetine hydrochloride comminution by gas stream, particle size distribution range is: 99% diameter is not more than 40 μ m, 90% diameter is not more than 25 μ m, and 50% diameter is not more than 10 μ m, and 5% diameter is not more than 5 μ m, for subsequent use, take by weighing recipe quantity duloxetine hydrochloride, sucrose, carboxymethyl starch sodium, starch mix homogeneously by prescription 3,5% hypromellose aqueous solution is done binding agent, the preparation soft material, be prepared into the pill core that carries that diameter is 0.425mm～1.4mm with extruding spheronizator, for subsequent use.Sealing coat coating solution preparation: the recipe quantity ketopyrrolidine is added 50% ethanol water (mass ratio) of recipe quantity, add again after the Polyethylene Glycol stirring and dissolving for subsequent usely, again Pulvis Talci, titanium dioxide are added, stir, low rate mixing half an hour continues to stir lower, carries out coating with fluid bed.Enteric coating preparation: take by weighing and add recipe quantity Pulvis Talci, titanium dioxide behind the medicinal alcohol dissolve complete that recipe quantity acroleic acid resin SD50, diethyl phthalate add recipe quantity and stir that making is uniformly dispersed carries out coating afterwards with fluid bed, obtain coated micropill, again the encapsulating capsule.
Prescription 3
Embodiment 4
With the duloxetine hydrochloride comminution by gas stream, particle size distribution range is: 99% diameter is not more than 50 μ m, 90% diameter is not more than 35 μ m, 50% diameter is not more than 20 μ m, 5% diameter is not more than 10 μ m, for subsequent use, take by weighing recipe quantity duloxetine hydrochloride, sucrose, lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mix homogeneously by prescription 4,3% hypromellose is done binding agent, POLYSORBATE 80 adds binding agent, the preparation soft material is prepared into the pill core that carries that diameter is 0.425mm～1.4mm with extruding spheronizator, and is for subsequent use.Sealing coat coating solution preparation: the recipe quantity hypromellose is added the water of recipe quantity, add again after the Polyethylene Glycol stirring and dissolving for subsequent usely, again Pulvis Talci is added, stir, low rate mixing half an hour continue to stir lower, carry out coating with fluid bed.Enteric coating preparation: take by weighing medicinal 95% dissolve with ethanol that recipe quantity methylacrylic acid resin copolymer, triethyl citrate add recipe quantity and add recipe quantity silicon dioxide, titanium dioxide, iron oxide yellow after fully and stir that making is uniformly dispersed carries out coating afterwards with fluid bed, obtain coated micropill, again the encapsulating capsule.
Prescription 4
Embodiment 5
With the duloxetine hydrochloride comminution by gas stream, particle size distribution range is: 99% diameter is not more than 50 μ m, 90% diameter is not more than 35 μ m, and 50% diameter is not more than 20 μ m, and 5% diameter is not more than 10 μ m, for subsequent use, take by weighing recipe quantity duloxetine hydrochloride, microcrystalline Cellulose, cross-linked pvp, sucrose, starch mix homogeneously by prescription 5,5% hypromellose is done binding agent, the preparation soft material, be prepared into the pill core that carries that diameter is 0.425mm～1.4mm with extruding spheronizator, for subsequent use.Sealing coat coating solution preparation: the recipe quantity hypromellose is added the purified water of recipe quantity, add again after the Polyethylene Glycol stirring and dissolving for subsequent usely, again Pulvis Talci, titanium dioxide are added, stir, low rate mixing half an hour continues to stir lower, carries out coating with fluid bed.The enteric coating preparation: take by weighing recipe quantity methacrylic resin class pressed powder OPADRY ENTERIC, the 80% medicinal alcohol solution stirring that adds recipe quantity makes and is uniformly dispersed, and stirs slowly 45 minutes again, carries out coating with fluid bed under the stirring.Complete layer coating solution preparation: the recipe quantity hypromellose is added the purified water of recipe quantity, add again after the Polyethylene Glycol stirring and dissolving for subsequent usely, again Pulvis Talci is added, stir, low rate mixing half an hour, continue to stir lower, carry out coating with fluid bed, obtain coated micropill, again the encapsulating capsule.
Prescription 5
Embodiment 6
With the duloxetine hydrochloride comminution by gas stream, particle size distribution range is: 99% diameter is not more than 40 μ m, 90% diameter is not more than 25 μ m, 50% diameter is not more than 20 μ m, 5% diameter is not more than 5 μ m, for subsequent use, take by weighing recipe quantity duloxetine hydrochloride, microcrystalline Cellulose, sucrose, cross-linking sodium carboxymethyl cellulose mix homogeneously by prescription 6,5% hypromellose aqueous solution is done binding agent, PLURONICS F87 is added bonding agent, the preparation soft material is prepared into the pill core that carries that diameter is 0.425mm～1.4mm with extruding spheronizator, and is for subsequent use.Sealing coat coating solution preparation: after the recipe quantity hypromellose being added the purified water dissolve complete of recipe quantity, again Pulvis Talci is added, stir, low rate mixing half an hour continue to stir lower, carry out coating with fluid bed.Enteric coating preparation: take by weighing recipe quantity aqueous dispersion Aqoat and add after the recipe quantity purified water is uniformly dispersed, add recipe quantity Pulvis Talci, titanium dioxide and stir that making is uniformly dispersed carries out coating afterwards with fluid bed, obtain coated micropill, again the encapsulating capsule.
Prescription 6
Embodiment 7
With the duloxetine hydrochloride comminution by gas stream, particle size distribution range is: 99% diameter is not more than 75 μ m, 90% diameter is not more than 50 μ m, 50% diameter is not more than 30 μ m, 5% diameter is not more than 10 μ m, for subsequent use, take by weighing recipe quantity duloxetine hydrochloride, sucrose, starch, microcrystalline Cellulose, cross-linked pvp, sodium lauryl sulphate mix homogeneously by prescription 7,5% hypromellose aqueous solution is done binding agent, the preparation soft material, be prepared into the pill core that carries that diameter is 0.425mm～1.4mm with extruding spheronizator, for subsequent use.Sealing coat coating solution preparation: after the recipe quantity hypromellose being added the purified water dissolve complete of recipe quantity, again with Pulvis Talci, stir, low rate mixing half an hour continue to stir lower, carry out coating with fluid bed.Enteric coating preparation: take by weighing the 95% medicinal alcohol dissolve complete that the recipe quantity acroleic acid resin adds recipe quantity, Polyethylene Glycol adds a small amount of water dissolution and adds after fully again and stir, and rear adding recipe quantity Pulvis Talci, titanium dioxide stir that making is uniformly dispersed carries out coating afterwards with fluid bed.Complete layer is prepared and coating according to the contagion gown mode, obtains coated micropill, at last encapsulating capsule again.
Prescription 7
Embodiment 8
With the duloxetine hydrochloride comminution by gas stream, particle size distribution range is: 99% diameter is not more than 75 μ m, 90% diameter is not more than 50 μ m, 50% diameter is not more than 30 μ m, 5% diameter is not more than 10 μ m, for subsequent use, take by weighing recipe quantity duloxetine hydrochloride, sucrose, microcrystalline Cellulose, carboxymethyl starch by prescription 8 and receive mix homogeneously, 5% hypromellose is done binding agent, after stirring in the PLURONICS F87 adding binding agent, the preparation soft material is prepared into the pill core that carries that diameter is 0.425mm～1.4mm with extruding spheronizator, and is for subsequent use.Sealing coat coating solution preparation: the recipe quantity hypromellose is added the water of recipe quantity, add again after the Polyethylene Glycol stirring and dissolving for subsequent usely, again Pulvis Talci, titanium dioxide are added, stir, low rate mixing half an hour continue to stir lower, carry out coating with fluid bed.Enteric coating preparation: after taking by weighing the 95% medicinal alcohol dissolve complete that recipe quantity EudragitL100-55 adds recipe quantity, Polyethylene Glycol adds after adding a small amount of water dissolution again, adds successively the recipe quantity Pulvis Talci and stirs that making is uniformly dispersed carries out coating afterwards with fluid bed.Complete layer carries out coating according to after contagion gown compound method (the Polyethylene Glycol does not add) preparation, obtains coated micropill, at last encapsulating capsule again.
Prescription 8
Embodiment 9
With the duloxetine hydrochloride comminution by gas stream, particle size distribution range is: 99% diameter is not more than 75 μ m, 90% diameter is not more than 50 μ m, and 50% diameter is not more than 30 μ m, and 5% diameter is not more than 10 μ m, for subsequent use, take by weighing recipe quantity duloxetine hydrochloride, sucrose, starch, cross-linked pvp, sodium lauryl sulphate mix homogeneously by prescription 9,5% hypromellose aqueous solution is done binding agent, the preparation soft material, be prepared into the pill core that carries that diameter is 0.425mm～1.4mm with extruding spheronizator, for subsequent use.Sealing coat coating solution preparation: the recipe quantity hypromellose is added the water of recipe quantity, add again after the Polyethylene Glycol stirring and dissolving for subsequent usely, again Pulvis Talci, titanium dioxide are added, stir, low rate mixing half an hour continue to stir lower, carry out coating with fluid bed.Enteric coating preparation: take by weighing and add the recipe quantity Pulvis Talci behind the 95% medicinal alcohol dissolve complete that recipe quantity EUDRAGIT L100, triethyl citrate add recipe quantity and stir that making is uniformly dispersed carries out coating afterwards with fluid bed. complete layer carries out coating after according to contagion gown compound method preparation (titanium dioxide does not add).The complete layer collocation method is with contagion gown identical (titanium dioxide does not add), and rear lasting stirring fluidized bed at elevated coating obtains coated micropill, again the encapsulating capsule.
Prescription 9
Embodiment 10
With the duloxetine hydrochloride comminution by gas stream, particle size distribution range is: 99% diameter is not more than 40 μ m, 90% diameter is not more than 25 μ m, 50% diameter is not more than 20 μ m, 5% diameter is not more than 5 μ m, for subsequent use, take by weighing recipe quantity duloxetine hydrochloride, microcrystalline Cellulose, sucrose, cross-linking sodium carboxymethyl cellulose mix homogeneously by prescription 6,5% hypromellose aqueous solution is done binding agent, PLURONICS F87 is added bonding agent, the preparation soft material is prepared into the pill core that carries that diameter is 0.425mm～1.4mm with extruding spheronizator, and is for subsequent use.Sealing coat coating solution preparation: after the recipe quantity hypromellose being added the purified water dissolve complete of recipe quantity, again Pulvis Talci is added, stir, low rate mixing half an hour continue to stir lower, carry out coating with fluid bed.Enteric coating preparation: take by weighing recipe quantity aqueous dispersion Aqoat and add after recipe quantity 50% ethanol water is uniformly dispersed, add again after triethyl citrate stirs, add at last recipe quantity Pulvis Talci, titanium dioxide and stir that making is uniformly dispersed carries out coating afterwards with fluid bed, obtain coated micropill, again the encapsulating capsule.
Prescription 10
Embodiment 11 releases are investigated
The capsule that embodiment 1 to 10 makes, investigate according to following stripping assay method respectively, with reference to 2010 editions appendix XC of Chinese Pharmacopoeia stripping I basket method, rotating speed 75 turns, method is as follows: the aqueous hydrochloric acid solution take 300ml concentration 0.1mol/l was as dissolution medium in front 2 hours, rapidly adding the 700mlPH values at 300 milliliters again after 2 hours is 6.8 buffer salt solution, measured the stripping result in 45 minutes, hydrochloric acid medium is respectively at 30 minutes, 60 minutes, 90 minutes, sampling in 120 minutes, it is 135 minutes in total time respectively in the buffer salt, 150 minutes, sampling in 165 minutes, external standard method is calculated the cumulative release amount, the results are shown in Table 1.
Table 1: release cumulative release result
Claims (11)
1. a duloxetine hydrochloride enteric coated-pellet is comprised of year pill core and the coatings that comprise duloxetine hydrochloride, it is characterized in that, contains disintegrating agent in the described year pill core.
2. duloxetine hydrochloride enteric coated-pellet according to claim 1 is characterized in that, the mass ratio of described disintegrating agent in carrying pill core is 1% to 10%.
3. duloxetine hydrochloride enteric coated-pellet according to claim 1 is characterized in that, the composition of described year pill core and quality proportioning are:
5～40 parts of duloxetine hydrochlorides;
30～80 parts of filleies;
1～10 part of disintegrating agent;
0.5～15 part of binding agent;
0～5 part of antiplastering aid;
0.01～5 part in surfactant.
4. duloxetine hydrochloride enteric coated-pellet according to claim 1 is characterized in that, described medicine carrying ball core diameter is 0.425mm～1.4mm.
5. duloxetine hydrochloride enteric coated-pellet according to claim 1, it is characterized in that, the particle size range of duloxetine hydrochloride medicine material is in described year pill core: 99% diameter is not more than 50 μ m, 90% diameter is not more than 35 μ m, 50% diameter is not more than 20 μ m, and 5% diameter is not more than 10 μ m.
6. duloxetine hydrochloride enteric coated-pellet according to claim 1 is characterized in that, described coatings is enteric layer and wraps in the sealing coat that carries between pill core and the enteric layer.
7. duloxetine hydrochloride enteric coated-pellet according to claim 6 is characterized in that, the component of described enteric layer and quality proportioning are:
70～100 parts of enteric materials;
0～15 part of plasticizer;
0～20 part of antiplastering aid;
0～10 part of opacifier.
8. duloxetine hydrochloride enteric coated-pellet according to claim 6 is characterized in that, described coatings also comprises the complete layer that wraps in outside the enteric layer.
9. duloxetine hydrochloride enteric coated-pellet according to claim 8 is characterized in that, the component of described sealing coat or complete layer and quality proportioning are:
70～100 parts of water-soluable gel materials;
0～20 part of antiplastering aid;
0～10 part of plasticizer;
0～10 part of opacifier;
10. capsule that is filled with the described duloxetine hydrochloride enteric coated-pellet of each claim of claim 1 to 9.
11. the preparation method of capsule according to claim 10, raw material is carried out micronization processes, reaching particle size range is distributed as: 99% diameter is not more than 50 μ m, 90% diameter is not more than 35 μ m, 50% diameter is not more than 20 μ m, 5% diameter is not more than 10 μ m, according to the prescription proportioning of carrying pill core, the preparation particle size range is the pill core that carries of 0.425mm～1.4mm, according to each coatings formulation ratio, carry out coating with the fluid bed mode, prepare coated micropill, again coated micropill encapsulating capsule is namely got described duloxetine hydrochloride enteric coated capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201110220256XA CN102908331A (en) | 2011-08-01 | 2011-08-01 | Duloxetine hydrochloride enteric capsules and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110220256XA CN102908331A (en) | 2011-08-01 | 2011-08-01 | Duloxetine hydrochloride enteric capsules and preparation method thereof |
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| CN102908331A true CN102908331A (en) | 2013-02-06 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201110220256XA Pending CN102908331A (en) | 2011-08-01 | 2011-08-01 | Duloxetine hydrochloride enteric capsules and preparation method thereof |
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Cited By (6)
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| CN103211777A (en) * | 2013-03-31 | 2013-07-24 | 北京万全阳光医学技术有限公司 | Pharmaceutic preparation of duloxetine hydrochloride and preparation method thereof |
| CN103393615A (en) * | 2013-07-24 | 2013-11-20 | 海南华益泰康药业有限公司 | Duloxetine enteric pellet and preparation method thereof |
| CN104107169A (en) * | 2014-07-12 | 2014-10-22 | 浙江华海药业股份有限公司 | Duloxetine hydrochloride medicinal composition and a preparation method thereof |
| CN104414993A (en) * | 2013-08-20 | 2015-03-18 | 天津药物研究院 | Duloxetine hydrochloride enteric micro-pellet capsule and preparation method thereof |
| CN105520920A (en) * | 2016-01-04 | 2016-04-27 | 浙江美华鼎昌医药科技有限公司 | Duloxetine hydrochloride capsule and preparation method thereof |
| JP2018172361A (en) * | 2016-10-14 | 2018-11-08 | 大原薬品工業株式会社 | Solid preparation containing duloxetine, having improved light stability |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103211777A (en) * | 2013-03-31 | 2013-07-24 | 北京万全阳光医学技术有限公司 | Pharmaceutic preparation of duloxetine hydrochloride and preparation method thereof |
| CN103393615A (en) * | 2013-07-24 | 2013-11-20 | 海南华益泰康药业有限公司 | Duloxetine enteric pellet and preparation method thereof |
| CN103393615B (en) * | 2013-07-24 | 2015-07-15 | 海南华益泰康药业有限公司 | Duloxetine enteric pellet and preparation method thereof |
| CN104414993A (en) * | 2013-08-20 | 2015-03-18 | 天津药物研究院 | Duloxetine hydrochloride enteric micro-pellet capsule and preparation method thereof |
| CN104107169A (en) * | 2014-07-12 | 2014-10-22 | 浙江华海药业股份有限公司 | Duloxetine hydrochloride medicinal composition and a preparation method thereof |
| CN105520920A (en) * | 2016-01-04 | 2016-04-27 | 浙江美华鼎昌医药科技有限公司 | Duloxetine hydrochloride capsule and preparation method thereof |
| CN105520920B (en) * | 2016-01-04 | 2018-09-07 | 浙江美华鼎昌医药科技有限公司 | Duloxetine hydrochloride capsule and preparation method thereof |
| JP2018172361A (en) * | 2016-10-14 | 2018-11-08 | 大原薬品工業株式会社 | Solid preparation containing duloxetine, having improved light stability |
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