CN102579408B - Doxycycline hydrochloride dual-release preparation and preparation method thereof - Google Patents
Doxycycline hydrochloride dual-release preparation and preparation method thereof Download PDFInfo
- Publication number
- CN102579408B CN102579408B CN 201210072362 CN201210072362A CN102579408B CN 102579408 B CN102579408 B CN 102579408B CN 201210072362 CN201210072362 CN 201210072362 CN 201210072362 A CN201210072362 A CN 201210072362A CN 102579408 B CN102579408 B CN 102579408B
- Authority
- CN
- China
- Prior art keywords
- micropill
- release
- doxycycline hydrochloride
- slowbreak
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical science, and particularly relates to a doxycycline hydrochloride dual-release preparation and a preparation method thereof. The preparation consists of micropills with different release performance, namely the preparation is formed by mixing 50 to 85 weight percent of quick-release micropill and 50 to 15 weight percent of sustained-release micropill. The preparation method comprises the following steps of: preparing micropill cores according to a formula, and preparing the quick-release micropills by using the micropill cores; preparing the sustained-release micropills by using the quick-release micropills; and filling the quick-release micropills and the sustained-release micropills into capsules in a ratio to obtain doxycycline hydrochloride dual-release capsules. Pharmacokinetic experiments in the dual-release capsule bodies indicate that medicines in the doxycycline hydrochloride dual-release capsules can be released twice when the doxycycline hydrochloride dual-release capsules are taken once every day, and the concentration of two-time peaks is close; the concentration peak of medicines in blood plasma is reduced by a dual-release model, the possibility of side effect is reduced, and the compliance of the administration of patients is improved; and due to the adoption of a new formula and a new process, the difference among batches is reduced, and the stability of samples is improved, so the doxycycline hydrochloride dual-release preparation is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of doxycycline hydrochloride preparation, particularly relate to two delivery formulations of a kind of doxycycline hydrochloride and preparation method thereof.
Technical background
Doxycycline hydrochloride is tetracycline antibiotics, and chemical name is 6-methyl-4-(dimethylamino)-3,5,10,12,12a-penta hydroxy group-1,11-dioxo-1,4,4a, 5,5a, 6,11,12a-octahydro-2-aphthacene carboxamide hydrochloride half ethanol semihydrate, its molecular formula is: C22H25ClN2O8. C2H6O. H2O, molecular weight are 512.94, doxycycline hydrochloride is faint yellow or yellow crystalline powder, odorless, bitter in the mouth.Easily molten in water or methanol, slightly soluble in ethanol or acetone, almost insoluble in chloroform.
Doxycycline hydrochloride is tetracycline antibiotics, and clinical use for many years.Its Pharmacological Mechanism is similar to tetracycline, mainly has been combined bacteriostasis with target protein by bacterial membrane, and antimicrobial spectrum and tetracycline, oxytetracycline are basic identical, and the inside and outside antimicrbial power of body is all strong than tetracycline, and oral absorption is good.Be mainly used in responsive gram positive bacteria and the upper respiratory tract infection due to gram negative bacilli, tonsillitis, biliary tract infection, lymphadenitis, honeycomb group inflammation, senile chronic bronchitis etc., also be used for the treatment of typhus fever, Qiang's parasitosis, mycoplasma pneumonia etc.
Due to doxycycline have higher fat-soluble, stronger to tissue penetration, often can cause a lot of side effect as the ordinary preparation of traditional specification (50mg, 100mg) of broad spectrum antibiotic.For example, can cause nausea, vomit, the gastrointestinal reaction such as stomachache, diarrhoea; Can make normal flora minimizing in human body, and cause vitamin deficiency, fungus breeding, xerostomia, pharyngitis, angular cheilitis and glossitis etc. occur.Therefore, need the new product of development to overcome above problem.
Summary of the invention
The technical problem to be solved in the present invention: for reducing the toxic and side effects of doxycycline hydrochloride, improve the compliance of medication, a kind of two release capsule preparations take doxycycline hydrochloride as principal agent and preparation method thereof are provided.
Technical scheme of the present invention:
The two release capsules of doxycycline hydrochloride of the present invention, described preparation has the performance that discharges medicine for twice, comprise fast release micropill part and slowbreak micropill part, this capsule is prepared from by doxycycline hydrochloride, filler, binding agent, filmogen, opacifier, slowbreak material, plasticizer, antiplastering aid, solubilizing agent etc.
Wherein,
(a) the ball core of fast release micropill and slowbreak micropill is identical, by doxycycline hydrochloride, filler, add again that binding agent etc. is rear is prepared into the medicine carrying micropill by extruding spheronization, gained micropill diameter control is at 0.3-1.5mm, and the micropill of preferred 0.6 ± 0.1mm scope is as the ball core of preparation rapid release or slowbreak micropill.
(b) fast release micropill is prepared under certain process conditions and is got by medicine carrying micropill and sealing coat prescription.The sealing coat adjuvant is selected one or several film forming coating materials, and adds the auxiliary material combination of plasticizer and opacifier.The smooth surface rounding of obtained micropill has good stability and mobility.
(c) slowbreak micropill, carried out the coating of slowbreak material by fast release micropill, coating material comprises ethyl cellulose, hydroxypropyl methylcellulose, the polyacrylic acid resin, Aquacoat, hydroxypropyl cellulose, the hydroxyethyl-cellulose acetyl cellulose, Cellulose Acetate Phthalate, CAP, the vinyl acetate phthalate ester, the hydroxypropyl methylcellulose phthalate ester, one or several in the hydroxypropyl methylcellulose succinate, also need add antiplastering aid simultaneously, plasticizer and solubilizing agent are to improve the stable of coating solution and to make preparation technology carry out smoothly.
With respect to immediate release section in the two release capsules of doxycycline hydrochloride, in fast release micropill, the percentage by weight of each component is: doxycycline hydrochloride 10-40%, filler 30-80%, binding agent 0.5-15%, sealing coat filmogen 0-15%, plasticizer A 0-5%, opacifier 0-10%;
With respect to slowbreak part in the two release capsules of doxycycline hydrochloride, in the slowbreak micropill, the percentage by weight of each component is: doxycycline hydrochloride 10-40%, filler 20-70%, binding agent 0.5-15%, sealing coat filmogen 0-15%, plasticizer A 0-5%, opacifier 0-10%, slowbreak material 0.5-30%, plasticizer B 0.3-5%, antiplastering aid 0.5-10%, solubilizing agent 0.1-3%.
Described fast release micropill or slowbreak micropill are the matrix type micropill, and effective ingredient is doxycycline hydrochloride;
Filler in described fast release micropill or slowbreak micropill is one or several in sucrose, lactose, mannitol, starch, microcrystalline Cellulose, Sargassum polysaccharides, chitosan,
Binding agent in described fast release micropill or slowbreak micropill is one or several in the mixed solution, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvidone, sodium carboxymethyl cellulose of water, dehydrated alcohol, water and ethanol,
Sealing coat filmogen in described fast release micropill or slowbreak micropill is one or several in Opadry I, Opadry II, Opadry AMB, Opadry MP, hydroxypropyl methylcellulose, hyprolose, polyvidone, polyvinyl alcohol,
Plasticizer A in described fast release micropill or slowbreak micropill is one or several in triethyl citrate, acetyltriethyl citrate, acetyl tributyl citrate, dibutyl sebacate, glyceryl triacetate, Polyethylene Glycol, propylene glycol,
Opacifier in described fast release micropill or slowbreak micropill is one or several in titanium dioxide, iron oxide red, iron oxide yellow,
Described slowbreak material be ethyl cellulose, hydroxypropyl methylcellulose, polyacrylic acid resin, Aquacoat, hydroxypropyl cellulose, hydroxyethyl-cellulose acetyl cellulose, Cellulose Acetate Phthalate, CAP, vinyl acetate phthalate ester, hydroxypropyl methylcellulose phthalate ester, refined gram should, one or several in hydroxypropyl methylcellulose succinate, polylactic acid, palm wax
Described plasticizer B is one or several in triethyl citrate, acetyltriethyl citrate, acetyl tributyl citrate, dibutyl sebacate, glyceryl triacetate, Polyethylene Glycol, diethyl phthalate, dibutyl phthalate, tristerin, tributyl citrate, diethyl succinate, fractionated coconut oil, propylene glycol
Described antiplastering aid is one or several in Pulvis Talci, colloidal silica, magnesium stearate, calcium stearate, magnesium silicate, glyceryl monostearate,
Described solubilizing agent is one or several in sodium lauryl sulphate, sorbitan fatty acid ester, poloxamer, Tween-20, Tween-60, Tween-80.
Filler preferably microcrystalline cellulose in fast release micropill wherein, the preferred hydroxypropyl methylcellulose solution of binding agent, the preferred hydroxypropyl methylcellulose of sealing coat filmogen and hydroxypropyl cellulose, the preferred Polyethylene Glycol of plasticizer A, the preferred titanium dioxide of opacifier.
Filler preferably microcrystalline cellulose in the slowbreak micropill, the preferred hydroxypropyl methylcellulose solution of binding agent, the preferred hydroxypropyl methylcellulose of sealing coat filmogen and hydroxypropyl cellulose, the preferred Polyethylene Glycol of plasticizer A, the preferred titanium dioxide of opacifier, slowbreak material optimization polypropylene acid resin, the preferred Polyethylene Glycol of plasticizer B and triethyl citrate, antiplastering aid preferably talc powder, the preferred Tween-80 of solubilizing agent.
The two release capsules of doxycycline hydrochloride of the present invention, its more excellent percentage by weight is as follows:
Fast release micropill: doxycycline hydrochloride 15-25%, filler microcrystalline Cellulose 65-75%, binding agent hydroxypropyl methylcellulose 1-2%, sealing coat filmogen hydroxypropyl methylcellulose 5-6%, plasticizer A Polyethylene Glycol 0.5-1.5%, opacifier titanium dioxide 2-3%;
Slowbreak micropill: doxycycline hydrochloride 10-20%, filler microcrystalline Cellulose 55-65%, binding agent hydroxypropyl methylcellulose 0.5-1.5%, sealing coat filmogen hydroxypropyl methylcellulose 4-5%, plasticizer A Polyethylene Glycol 0.5%-1.5%, opacifier titanium dioxide 2-3%, slowbreak material polyacrylic acid resin 9-11%, plasticizer B Polyethylene Glycol 0.5%-1.5%, antiplastering aid Pulvis Talci 4-6%, solubilizing agent Tween-80 0.1-0.6%.
The two release capsules of doxycycline hydrochloride of the present invention are the piller forms of micropill of packing in capsule, and wherein micropill comprises ball core and coating, and the preparation method of ball core is as follows:
Medicine and filler are crushed to certain particle size range, by after 80-100 eye mesh screens in stirring mixer after mix homogeneously, add binding agent, make soft material, the medicine carrying micropill that spheronization makes uniform particle diameter is extruded in employing, according to the cylindrical length that extruding forms, the micropill particle diameter is controlled in the scope of 0.3-1.5mm, through preferably controlling particle diameter at 0.6 ± 0.1mm.
The two release capsules of doxycycline hydrochloride of the present invention, coating method is as follows:
Preferred coating material is adopted fluidized bed coating or coating pan coating, be injected into fluid bed after the clothing membrane material atomize under a suitable pressure, the clothing of coating material formation at a certain temperature film is attached on micropill.Micropill can obtain the uniform medicine carrying micropill of coating under certain fluidizing velocity.Micropill can improve the stability of clothing film through the post processing of placement at a certain temperature, reduces micropill for the impact of the external environment factor such as illumination, high temperature, humidity.
The two release capsules of doxycycline hydrochloride of the present invention, in capsule, the mass ratio of contained fast release micropill and slowbreak micropill is between 9: 1 to 1: 1, and preferred mass was than 5: 2.
In the described pair of delivery formulations, the effective dose of doxycycline hydrochloride between 20-100mg, is preferably 40mg, to adapt to different weight crowd's use, has close or identical body giving drugs into nose for dynamic characteristic during the corresponding different crowd of different size.
In the two release capsules of doxycycline hydrochloride of the present invention, the shared part by weight of fast release micropill is at 50-85%, and the part by weight of slowbreak micropill is at 50-15%.
Positive beneficial effect of the present invention:
(1) the two release capsules of doxycycline hydrochloride of the present invention, add opacifier in sealing coat, improved the stability of photosensitizer doxycycline; The slowbreak layer adopts the prescription after optimizing, and the coating material consumption greatly reduces.The vitro release test of said preparation shows, its release performance stable uniform, and between batch, the release relative standard deviation is less than 3%, referring to Fig. 1.Its therapeutic effect can be stablized and control the plasma drug level peak value with suitable each serving the ordinary preparation with same size, reduces side effect and addiction that medicine brings, improves the bioavailability of medicine, improves the compliance of patient's medication.
(2) of the present invention couple of release capsule preparation technology simplifies, adopt low temperature to extrude spheronizator and fluidized-bed process, productive rate reaches 90-100%, and the product effect is high, and spheronization is extruded in employing can reduce the loss of doxycycline hydrochloride crude drug in preparation process than lamination medicine-feeding method.The present invention can complete the amplification production of 10000-30000 unit under laboratory scale, can prepare the two release capsules of doxycycline hydrochloride of 20-100mg different size, to adapt to the needs of different crowd.
(3) of the present invention pair of release capsule body giving drugs into nose shows for dynamic experiment, takes every day and once can produce twice drug release, and wherein immediate release section produces release at short notice, and plasma drug level reaches first peak value; Through after about 2.5 h, beginning discharges for the second time, produces second plasma drug level peak value, and the concentration of two minor peaks is close.The body giving drugs into nose shows for dynamics research, the bioavailability equivalence of said preparation and ordinary preparation, can not produce the problem that reduces bioavailability because of the effect of part slowbreak, its pair discharges model and reduced blood plasma Chinese medicine peak concentration, reduce the possibility that has side effects, only need take once every day, improved the compliance of patient's medication.
(4) of the present invention pair of release capsule accelerated test in stability study is investigated, in 6 months, property stability, medicament contg, related substance are all in controlled range, while, influence factor in stability study tested the investigation under high temperature, high humidity and strong illumination condition, functional, suitability for industrialized production.Referring to table 1-table 3.
Description of drawings
The vitro release curve that the two delivery formulations of Fig. 1 doxycycline hydrochloride of the present invention are three batches.
The specific embodiment
Be below the specific embodiment of the present invention, embodiment is for further describing the present invention rather than restriction the present invention.All and technical scheme equivalence of the present invention all belongs to protection scope of the present invention.
Two release capsules of embodiment 1 doxycycline hydrochloride and preparation method thereof
First prepare pastille piller ball core by formula, prepare fast release micropill by piller ball core, then prepare the slowbreak micropill by fast release micropill, at last fast release micropill and slowbreak micropill are distinguished filled capsules in proportion, namely get the two release capsules of doxycycline hydrochloride.
(1) ball core preparation process
Ball core prescription: microcrystalline Cellulose 640g, doxycycline hydrochloride 177g, the hydroxypropyl methylcellulose solution 640g of 2% (w/w).
Preparation process: doxycycline hydrochloride and filler microcrystalline Cellulose are crushed to certain particle size range, excessively mixed 30 minutes in stirring mixer after 80 eye mesh screens, add 2% hydroxypropyl methylcellulose solution, make soft material.Open Cryo Refrigerator, temperature is controlled at 4-15 ℃, after 10min, soft material is put into the cryogenic high pressure extruder, selecting sieve aperture is the sieve plate of 0.9-1.0mm, and extruded velocity is adjusted to 40rpm, forms the cylindrical soft material of moderate length, in spheronizator with the round as a ball 10min of the speed of 1800rpm, form the medicine carrying micropill of uniform particle diameter, according to the cylinder length of shearing, dry rear micropill particle diameter is controlled at 0.4-1.0mm.Take the productive rate of coating process as evaluation index, the micropill of preferable particle size 0.6 ± 0.1mm carries out coating, places 50 ℃ of dry 15h in baking oven, and the micropill of getting the 20-40 mesh sieve carries out the uniformity and water content inspection, qualified after, pill core is standby as carrying.
(2) fast release micropill preparation process
Fast release micropill prescription: carry pill core 800g, hydroxypropyl methylcellulose 48g, titanium dioxide 24g, Polyethylene Glycol 8g, deionized water 720g.
Preparation process: under agitation add hydroxypropyl methylcellulose and Polyethylene Glycol in deionized water, be dissolved to clarification, add titanium dioxide, continue to stir 1h, cross 40 eye mesh screens, get the sealing coat coating solution.
Get medicine carrying fine pellet core 800g and put into fluid bed, regulate inlet temperature to 55 ℃, adjust approximately 70m of intake
3* h
-1The sealing coat coating solution that configures is added to aerochamber atomizing coating by the end mode of spraying with the flow velocity of 2ml/min with peristaltic pump, atomizing pressure is 1.4bar, improve gradually feed flow speed to 8ml/min, until the coating solution bag is complete, place 60 ℃ of dry 2h in convection oven after coating finishes, namely get fast release micropill.
(3) slowbreak micropill preparation process
Slowbreak micropill prescription: fast release micropill 400g, polyacrylic acid resin 50g, Polyethylene Glycol 5g, Pulvis Talci 22.5g, Polysorbate 2.5g, 95%(mass ratio) ethanol 800ml.
Preparation process: get 95% ethanol and add polyacrylic acid resin, Polyethylene Glycol, Polysorbate under stirring, be dissolved to clarification, add Pulvis Talci, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution.
Get fast release micropill and be placed in fluid bed, regulate approximately 80m of inlet temperature to 50 ℃, dry air flow
3* h
-1Get above-mentioned coating solution, pump into aerochamber atomizing coating (atomizing pressure is as 1.8bar) with peristaltic pump take end spray mode 1.5ml/min, progressively improve feed flow speed to 8ml/min, until the coating solution bag is complete, coating is put into 50 ℃ of dry 2h of convection oven after finishing, and chooses the piller of 18-40 mesh sieve, check character and release, namely get the slowbreak micropill after qualified.
(4) the two release capsule fills of doxycycline hydrochloride
Fast release micropill and slowbreak micropill are packed into respectively capsule by the weight ratio of 5: 2, namely get the two release capsules of doxycycline hydrochloride.
Through adjusting, in this example in the two release capsules of doxycycline hydrochloride the percentage by weight of each component be:
Fast release micropill: doxycycline hydrochloride 19.4%, filler 70.1%, binding agent 1.4%, sealing coat filmogen 5.5%, plasticizer A 0.9%, opacifier 2.7%;
Slowbreak micropill: doxycycline hydrochloride 16.2%, filler 58.4%, binding agent 1.2%, sealing coat filmogen 4.5%, plasticizer A 0.8%, opacifier 2.3%, slowbreak material 10.5%, plasticizer B 1.1%, antiplastering aid 4.7%, solubilizing agent 0.4%.
Total effective dose of two every the hydrochloric doxycycline of release capsule of the doxycycline hydrochloride that this example obtains be 40mg(in anhydrous without the ethanol doxycycline), be applicable to the struvite skin lesion such as acne erythematosa, rosacea; Oral, once a day, each 1, morning, (medicine) being taken before meal use, preferably took 1-2 hour ante cibum.
Two release capsules of embodiment 2 doxycycline hydrochloride and preparation method thereof
(1) ball core prescription: microcrystalline Cellulose 640g, doxycycline hydrochloride 177g, 2% (w/w) povidone solution 640g.
Preparation process: doxycycline hydrochloride and microcrystalline Cellulose are pulverized, after mixing 30 minutes after 80 eye mesh screens in stirring mixer, added povidone solution, make soft material.Open Cryo Refrigerator, temperature is controlled at 4-15 ℃, after 10min, soft material being put into the cryogenic high pressure extruder is the sieve plate of 0.9-1.0mm by sieve aperture, extruded velocity is adjusted to 40rpm, form the cylindrical soft material of moderate length, with the round as a ball 10min of the speed of 1800rpm, form the medicine carrying micropill of uniform particle diameter in spheronizator, according to the cylinder length of shearing, dry rear micropill particle diameter is controlled in the scope of 0.4-1.0mm.Take the productive rate of coating process as evaluation index, the micropill of preferable particle size 0.6 ± 0.1mm carries out coating, puts into 50 ℃ of dry 15h of baking oven, and the micropill of getting the 20-40 mesh sieve carries out the uniformity and water content inspection, and it is standby that pill core is carried in qualified rear conduct.
(2) fast release micropill prescription: carry pill core 800g, Opadry I 80g, deionized water 720g.
Preparation process: add Opadry I under stirring in deionized water, continue to stir 1h, cross 40 eye mesh screens, get the sealing coat coating solution.Get medicine carrying fine pellet core 800g and put into fluid bed, regulate inlet temperature to 60 ℃, intake is 70m approximately
3* h
-1, the sealing coat coating solution that configures is first added aerochamber atomizing coating, atomizing pressure 1.6bar with the flow velocity of 1.5ml/min with peristaltic pump by the end mode of spraying, improve gradually feed flow speed to 7ml/min, until the coating solution bag is complete.Place 60 ℃ of dry 2h in convection oven after coating finishes, namely get fast release micropill.
(3) slowbreak micropill prescription: fast release micropill 400g, the suitable MP 160g of refined gram, deionized water 640g.
Preparation process: add the suitable MP of refined gram under stirring in deionized water, continue to stir 1h, cross 40 eye mesh screens,
Slowbreak layer coating solution.Get fast release micropill and be placed in fluid bed, regulate approximately 85m of inlet temperature to 50 ℃, dry air flow
3* h
-1Get above-mentioned coating solution, pump into aerochamber atomizing coating (atomizing pressure is as 1.6bar) with peristaltic pump take end spray mode 1.5ml/min, progressively improve feed flow speed complete to the coating solution bag to 7ml/min, coating is put into 50 ℃ of dry 2h of convection oven after finishing, choose the piller of 18-40 mesh sieve, checked character and release, namely got the slowbreak micropill after qualified.
(4) the two release capsule fills of doxycycline hydrochloride
Fast release micropill and slowbreak micropill are packed into respectively capsule by the weight ratio of 15: 7, namely get the two release capsules of doxycycline hydrochloride.
Two release capsules of embodiment 3 doxycycline hydrochloride and preparation method thereof
(1) ball core prescription: microcrystalline Cellulose 640g, doxycycline hydrochloride 177g, polyvinylpolypyrrolidone 20g, 2% hydroxypropyl methylcellulose aqueous solution 640g.
Preparation process: doxycycline hydrochloride, microcrystalline Cellulose and polyvinylpolypyrrolidone are pulverized, excessively mixed after 30 minutes in stirring mixer after 80 mesh sieves, add 640g hydroxypropyl methylcellulose aqueous solution, make soft material.Open Cryo Refrigerator, temperature is controlled at 4-15 ℃, after 10min, soft material is put into the cryogenic high pressure extruder by the sieve plate sieve aperture of 0.9-1.0mm, extruded velocity is adjusted to 40rpm, form the cylindrical soft material of moderate length, with the round as a ball 10min of the speed of 1800rpm, form the medicine carrying micropill of uniform particle diameter in spheronizator, according to the cylindrical length of shearing, dry rear micropill particle diameter is controlled at 0.4-1.0mm.Take the productive rate of coating process as evaluation index, preferable particle size is carried out coating at the micropill of 0.6 ± 0.1mm, places 50 ℃ of dry 15h in baking oven, and the micropill of getting the 20-40 mesh sieve carries out the uniformity and water content inspection, and it is standby that pill core is carried in qualified rear conduct.
(2) fast release micropill prescription:
Carry pill core 800g, hydroxypropyl methylcellulose 120g, deionized water 2000g.
Preparation process: get the deionized water of recipe quantity, add hydroxypropyl methylcellulose under stirring, get the sealing coat coating solution.Get medicine carrying fine pellet core 800g and put into fluid bed, regulate inlet temperature to 45 ℃, adjust approximately 80m of intake
3* h
-1The sealing coat coating solution that configures is added to aerochamber atomizing coating, atomizing pressure 1.8bar by the end mode of spraying with the flow velocity of 1.5ml/min with peristaltic pump, improve gradually feed flow speed to 10ml/min, until the coating solution bag is complete, place 60 ℃ of dry 2h in convection oven after coating finishes, namely get fast release micropill.
(3) slowbreak micropill prescription: fast release micropill 400g, the Aquacoat 160g of solid content 15%.
Preparation process: get fast release micropill and be placed in fluid bed, regulate approximately 80m of inlet temperature to 45 ℃, dry air flow
3* h
-1Get Aquacoat, it is 15% suspension that thin up becomes solid content, pump into aerochamber atomizing coating (atomizing pressure is as 1.6bar) with peristaltic pump take end spray mode 1.5ml/min, progressively improve feed flow speed complete to the coating solution bag to 5ml/min, place in convection oven after coating finishes and solidify 15h under 45 ℃ of conditions, chose the piller of 18-40 mesh sieve, check character and release, namely get the slowbreak micropill after qualified.
(4) the two release capsule fills of doxycycline hydrochloride
Fast release micropill and slowbreak micropill are packed into respectively capsule by the weight ratio of 25: 9, namely get the two release capsules of doxycycline hydrochloride.
Two release capsules of embodiment 4 doxycycline hydrochloride and preparation method thereof
(1) ball core prescription: sugar pill (30-35 order) 760g, doxycycline hydrochloride 200g, hydroxypropyl methylcellulose 40g, deionized water 1000g.
Preparation process: get the deionized water of recipe quantity, add hydroxypropyl methylcellulose under stirring, be dissolved to clarification, add doxycycline hydrochloride, continue to stir 1h, cross 40 eye mesh screens, get the medicine layer coating solution.
Get sugar pill celphere 760g and put into fluid bed, regulate inlet temperature to 50 ℃, adjust approximately 60m of intake
3* h
-1The medicine layer coating solution that configures is added to aerochamber atomizing coating, atomizing pressure 1.0bar by the end mode of spraying with the flow velocity of 2ml/min with peristaltic pump, improve gradually feed flow speed complete to the coating solution bag to 6ml/min, place 60 ℃ of dry 2h in convection oven after coating finishes, namely get medicine layered pills core.
(2) fast release micropill prescription: carry pill core 1000g, Opadry beige 100g, deionized water 900g.
Preparation process: get the deionized water of recipe quantity, add Opadry beige under stirring, continue to stir 1h, cross 40 eye mesh screens, get the sealing coat coating solution.Get the medicine carrying fine pellet core and put into fluid bed, regulate inlet temperature to 60 ℃, adjust approximately 70m of intake
3* h
-1The sealing coat coating solution that configures is added to aerochamber atomizing coating, atomizing pressure 1.6bar by the end mode of spraying with the flow velocity of 1.5ml/min with peristaltic pump, improve gradually feed flow speed complete to the coating solution bag to 7ml/min, place 60 ℃ of dry 2h in convection oven after coating finishes, namely get fast release micropill.
(3) slowbreak micropill prescription: fast release micropill 400g, Eudragit L30D-55 200g, triethyl citrate 9g, Pulvis Talci
31g, deionized water 200ml.
Preparation process: the deionized water of getting recipe quantity, add polyacrylic resin aqueous dispersion Eudragit L30D-55(polyacrylic resin aqueous dispersion under stirring, the enteric layers slow-release material), triethyl citrate, Pulvis Talci, continue to stir 1h, cross 40 eye mesh screens, get slowbreak layer coating solution.Get fast release micropill and be placed in fluid bed, regulate approximately 70m of inlet temperature to 40 ℃, dry air flow
3* h
-1Get above-mentioned coating solution, pump into aerochamber atomizing coating (atomizing pressure is as 1.6bar) with peristaltic pump take end spray mode 2ml/min, progressively improve feed flow speed complete to the coating solution bag to 5ml/min, after finishing, places coating 50 ℃ of dry 2h in convection oven, choose 18-40 mesh sieve piller, checked character and release, namely got the slowbreak micropill after qualified.
(4) the two release capsule fills of doxycycline hydrochloride
Fast release micropill and slowbreak micropill are distinguished filled capsules by weight the ratio of 12: 5, namely get the two release capsules of doxycycline hydrochloride.
Experimental example 5: release experiment
Prepared micropill as specimen, carries out the release experiment in the embodiment 1, and method is as follows:
Get specimen, test (2010 editions two appendix X D the second methods of Chinese Pharmacopoeia) according to the drug release determination method, adopt the dissolution determination subtraction unit, rotating speed is 75rpm, temperature is 37 ℃, under release medium was seen, detection method was ultraviolet spectrophotometry, and sampling time point is: 15 minutes, 30 minutes, 60 minutes, 120 minutes, 135 minutes, 150 minutes, 180 minutes, 240 minutes.Get solution at each time point appropriate, filter, get subsequent filtrate as need testing solution, adopt external standard method to calculate not in the same time burst size.
Acid phase: sample discharged in the hydrochloric acid solution of pH 1.1,750ml in 0～2 hour;
The 6.0 buffer stages of pH: in the time of 2 hours, add the 200mM phosphate buffer (wherein containing the acid of 3g sodium hydroxide in order to the neutralizing acid stage) of 200ml in the 750ml release medium more, regulate pH of buffer to 6.0; Drug release carried out in this phosphate buffer in 2～4 hours, and the medium cumulative volume is 950ml.
Experimental result shows: the two delivery formulations of this doxycycline hydrochloride are 2 hours cumulative release degree approximately 77% in acid, and 2 hours cumulative release degree reach 100.2% in the buffer of pH=6.0.Referring to accompanying drawing 1, in figure, this capsule of explanation has two release behaviors, and the slowbreak micropill has pH sensitivity, can discharge by the ad-hoc location in human body, and between different batches, difference is less.
Embodiment 2,3,4 product, under the same test condition, experimental result is identical with embodiment 1, all meets the requirements.
Experimental example 6: stability experiment
Adopt the capsule of embodiment 1 preparation, carry out influence factor's test (referring to 2010 editions two appendix XI X C of Pharmacopoeia of People's Republic of China) in the conventional medicine study on the stability, result shows that this product has good stability.
The stability of the two delivery formulations of doxycycline hydrochloride under the high heat condition of table 1
The stability of the two delivery formulations of doxycycline hydrochloride under table 2 super-humid conditions
The stability of the two delivery formulations of doxycycline hydrochloride under table 3 strong illumination condition
Claims (4)
1. the two release capsules of doxycycline hydrochloride, comprise fast release micropill and slowbreak micropill, it is characterized in that:
In described fast release micropill, the percentage by weight of each component is: doxycycline hydrochloride 15-25%, filler microcrystalline Cellulose 65-75%, binding agent hydroxypropyl methylcellulose 1-2%, sealing coat filmogen hydroxypropyl methylcellulose 5-6%, plasticizer A Polyethylene Glycol 0.5-1.5%, opacifier titanium dioxide 2-3%;
In the slowbreak micropill, the percentage by weight of each component is: doxycycline hydrochloride 10-20%, filler microcrystalline Cellulose 55-65%, binding agent hydroxypropyl methylcellulose 0.5-1.5%, sealing coat filmogen hydroxypropyl methylcellulose 4-5%, plasticizer A Polyethylene Glycol 0.5%-1.5%, opacifier titanium dioxide 2-3%, slowbreak material polyacrylic acid resin 9-11%, plasticizer B Polyethylene Glycol 0.5%-1.5%, antiplastering aid Pulvis Talci 4-6%, solubilizing agent Tween-80 0.1-0.6%;
The shared weight of fast release micropill is 50-85%, and the weight of slowbreak micropill is 50-15%;
Total effective dose of the doxycycline hydrochloride in the two release capsules of described every doxycycline hydrochloride is 20-100mg.
2. two release capsules of described doxycycline hydrochloride according to claim 1, is characterized in that: the preferred 40mg of total effective dose of the doxycycline hydrochloride in the two release capsules of described every doxycycline hydrochloride.
3. the preparation method of the two release capsules of the described doxycycline hydrochloride of claim 1 or 2, it is characterized in that: first prepare fine pellet core, prepare fast release micropill by fine pellet core, prepare the slowbreak micropill by fast release micropill again, at last fast release micropill and slowbreak micropill are mixed in proportion rear filled capsules, obtain the two release capsules of doxycycline hydrochloride;
(1) fine pellet core
Fine pellet core prescription: microcrystalline Cellulose 640g, doxycycline hydrochloride 177g, the hydroxypropyl methylcellulose solution 640g of 2%w/w;
Preparation process: doxycycline hydrochloride and the microcrystalline Cellulose of recipe quantity are pulverized, and mix homogeneously after 80 mesh sieves, add hydroxypropyl methylcellulose solution excessively, makes soft material; The medicine carrying micropill that spheronization makes uniform particle diameter is extruded in employing, and extruding forms cylinder, and the micropill particle diameter is controlled at 0.3-1.5mm;
(2) fast release micropill
Fast release micropill prescription: carry pill core 800g, hydroxypropyl methylcellulose 48g, titanium dioxide 24g, Polyethylene Glycol 8g, deionized water 720g;
Preparation process: under agitation add hydroxypropyl methylcellulose and the Polyethylene Glycol of recipe quantity in the deionized water, be dissolved to clarification, add titanium dioxide, continue to be stirred to mix homogeneously, obtain the sealing coat coating solution; Get medicine carrying fine pellet core 800g and put into fluid bed, regulate the fluid bed parameter to suitable, the sealing coat coating solution that configures is added aerochamber atomizing coating with peristaltic pump by spray gun, drying namely gets fast release micropill;
(3) slowbreak micropill
Slowbreak micropill prescription: fast release micropill 400g, polyacrylic acid resin 50g, Polyethylene Glycol 5g, Pulvis Talci 22.5g, Tween-80 2.5g, the ethanol 800ml of 95% mass ratio;
Preparation process: get 95% ethanol and add polyacrylic acid resin, Polyethylene Glycol, Tween-80 under stirring, be dissolved to clarification, add Pulvis Talci, continue to be stirred to mix homogeneously, get slowbreak layer coating solution; Get fast release micropill and be placed in fluid bed, regulate the fluid bed parameter to suitable, the sealing coat coating solution that configures is added aerochamber atomizing coating with peristaltic pump by spray gun, it is dry after coating finishes, choose the micropill of prescribed limit, check character and release, namely get the slowbreak micropill after qualified;
(4) the two release capsule fills of doxycycline hydrochloride
Fast release micropill and slowbreak micropill are packed into respectively capsule by the weight ratio of 5: 2, namely get the two release capsules of doxycycline hydrochloride.
4. preparation method according to claim 3, is characterized in that, described micropill particle diameter is controlled at 0.6 ± 0.1mm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210072362 CN102579408B (en) | 2012-03-19 | 2012-03-19 | Doxycycline hydrochloride dual-release preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201210072362 CN102579408B (en) | 2012-03-19 | 2012-03-19 | Doxycycline hydrochloride dual-release preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102579408A CN102579408A (en) | 2012-07-18 |
| CN102579408B true CN102579408B (en) | 2013-06-05 |
Family
ID=46469020
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201210072362 Active CN102579408B (en) | 2012-03-19 | 2012-03-19 | Doxycycline hydrochloride dual-release preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102579408B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106031715B (en) * | 2015-04-17 | 2019-11-05 | 力品药业（厦门）有限公司 | A kind of Doxycycline Hyclate sustained release preparation and preparation method thereof |
| CN106974966A (en) * | 2016-01-18 | 2017-07-25 | 北京海吉星医疗科技有限公司 | Double release capsules of a kind of body resistance-strengthening Zhenqi and preparation method thereof |
| CN112472679A (en) * | 2020-12-02 | 2021-03-12 | 上海汉维生物医药科技有限公司 | Double-release tablet and preparation method thereof |
| CN113069434A (en) * | 2021-03-11 | 2021-07-06 | 绍兴文理学院元培学院 | Tofacitinib citrate controlled-release capsule and preparation method thereof |
| CN113546049B (en) * | 2021-04-30 | 2023-03-17 | 贵州汉方药业有限公司 | Flexible pill medicine adhesive and flexible pill prepared by using same |
| CN115487154B (en) * | 2022-11-17 | 2023-02-21 | 山东国邦药业有限公司 | Preparation method of doxycycline hydrochloride granules |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003086366A1 (en) * | 2002-04-12 | 2003-10-23 | F H Faulding & Co Limited | An improved modified release preparation |
| US6958161B2 (en) * | 2002-04-12 | 2005-10-25 | F H Faulding & Co Limited | Modified release coated drug preparation |
| CN101596162A (en) * | 2008-06-04 | 2009-12-09 | 永信药品工业(昆山)有限公司 | Doxycycline hyclate enteric-coated pellet |
| CN101933913A (en) * | 2010-09-16 | 2011-01-05 | 孙卫东 | Dexmethylphenidate hydrochloride dual-release preparation and preparation method thereof |
| CN102091051A (en) * | 2009-12-14 | 2011-06-15 | 北京科信必成医药科技发展有限公司 | Allopurinol dual-release preparation and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2514879C (en) * | 2003-01-03 | 2014-09-16 | Shire Laboratories Inc. | Two or more enteric materials to regulate drug release |
-
2012
- 2012-03-19 CN CN 201210072362 patent/CN102579408B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003086366A1 (en) * | 2002-04-12 | 2003-10-23 | F H Faulding & Co Limited | An improved modified release preparation |
| US6958161B2 (en) * | 2002-04-12 | 2005-10-25 | F H Faulding & Co Limited | Modified release coated drug preparation |
| CN101596162A (en) * | 2008-06-04 | 2009-12-09 | 永信药品工业(昆山)有限公司 | Doxycycline hyclate enteric-coated pellet |
| CN102091051A (en) * | 2009-12-14 | 2011-06-15 | 北京科信必成医药科技发展有限公司 | Allopurinol dual-release preparation and preparation method thereof |
| CN101933913A (en) * | 2010-09-16 | 2011-01-05 | 孙卫东 | Dexmethylphenidate hydrochloride dual-release preparation and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102579408A (en) | 2012-07-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102579408B (en) | Doxycycline hydrochloride dual-release preparation and preparation method thereof | |
| JP3140764B2 (en) | Pulsatile once-daily release system of minocycline | |
| EP1976489B1 (en) | Multiple unit type sustained release oral formulation comprising zaltoprofen and process for the preparation thereof | |
| CN1886119B (en) | Pantoprazole multiparticulate formulations | |
| US7074417B2 (en) | Multiple-delayed release anti-viral product, use and formulation thereof | |
| US20020068085A1 (en) | Antiviral product, use and formulation thereof | |
| CN102579367B (en) | Topiramate sustained-release drug composition, method for preparing same and application of Topiramate sustained-release drug composition | |
| CN103054832B (en) | Minocycline hydrochloride sustained-release capsule and preparation method thereof | |
| CN107823189B (en) | Potassium chloride sustained-release pellet and preparation method and application thereof | |
| WO2013139266A1 (en) | Joint product containing phentermine and topiramate and preparation method therefor | |
| CN101623269A (en) | Oral sustained release granules | |
| CN103976972A (en) | Zolpidem tartrate oral pulse controlled-release delivery system and preparation method thereof | |
| CN101596162B (en) | Doxycycline hyclate enteric-coated pellet | |
| CN101933913A (en) | Dexmethylphenidate hydrochloride dual-release preparation and preparation method thereof | |
| CN102824331A (en) | Zaleplon double-release capsule and preparation method thereof | |
| CN106074442B (en) | A kind of doxycycline hyclate enteric-coated piller and preparation method thereof | |
| CN106806353B (en) | Iguratimod sustained-release capsule and preparation method thereof | |
| CN107865828B (en) | Oral colon positioning preparation for preventing and treating colon cancer metastasis, preparation method and application thereof | |
| CN107625733B (en) | Clarithromycin granules capable of being swallowed without water and preparation method thereof | |
| CN107530290A (en) | Slow release medical composition containing rivastigmine | |
| CN107072956A (en) | A kind of Pharmaceutical composition containing dabigatran etcxilate, its preparation method, solid pharmaceutical preparation and purposes | |
| CN104644565A (en) | Doxycycline hydrochloride drug-containing small pills and preparation method thereof | |
| CN114557976B (en) | Scutellarin sustained release tablet and preparation method thereof | |
| WO2013139292A1 (en) | Joint product containing synephrine and topiramate | |
| CN111557929B (en) | Dexmethylphenidate hydrochloride multiple-release preparation and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: ZHONGSHUAI PHARMACEUTICAL SCIENCE AND TECHNOLOGY I Free format text: FORMER NAME: ZHONGSHUAI PHARMACEUTICAL SCI+TECH DEVELOPMENT CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 18, building 7, block A, 450001 Holly Road, Gaoxin District, Henan, Zhengzhou Patentee after: ZHONGSHUAI PHARMACEUTICAL SCI & TECH INCORPORATED CO., LTD. Address before: 18, building 7, block A, 450001 Holly Road, Gaoxin District, Henan, Zhengzhou Patentee before: Henan Zhongshuai Pharmaceutical Science Development Co., Ltd. |