CN104434918A - Oxycodone hydrochloride and ibuprofen compound multilayer tablet, and preparation method thereof - Google Patents
Oxycodone hydrochloride and ibuprofen compound multilayer tablet, and preparation method thereof Download PDFInfo
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- CN104434918A CN104434918A CN201310422029.4A CN201310422029A CN104434918A CN 104434918 A CN104434918 A CN 104434918A CN 201310422029 A CN201310422029 A CN 201310422029A CN 104434918 A CN104434918 A CN 104434918A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
The invention belongs to the field of pharmaceutical preparations, and discloses an oxycodone hydrochloride and ibuprofen compound multilayer tablet, and a preparation method thereof. According to the ibuprofen and oxycodone multilayer tablet, one layer is an ibuprofen layer and comprises ibuprofen and a pharmaceutically acceptable auxiliary material, the other layer is an oxycodone layer and comprises oxycodone and a pharmaceutically acceptable auxiliary material, and the adhesive of the oxycodone layer can not select polyvinylpyrrolidone. According to the present invention, the oxycodone and the ibuprofen are respectively positioned in different layers, are not degraded at the room temperature and the high temperature, and have good stability and good quality controllability. In the prior art, in the general compound tablets, in the presence of the ibuprofen, coexisting of the oxycodone and the adhesive or the oxycodone, the adhesive and the lubricant can cause problems of severe main drug degradation severe and uncontrollable quality, such that the mass production is not easily achieved. With the method of the present invention, the problems in the prior art are avoided.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to oxycodone hydrochloride and ibuprofen compound recipe multilayer tablet and preparation method thereof.
Background technology
Pain belongs to a kind of commonly encountered diseases, and its sickness rate in China adult, up to more than 40%, can occur in each organ of health, as dysmenorrhea, and headache, migraine, cancer pain, musculoskeletal pain, postoperative pain, the pain etc. of empyrosis.Current clinical conventional analgesic has two kinds: one class to be take morphine as the narcosis analgesic of representative, and another kind of is take aspirin as the antipyretic analgesic of representative.Although the former analgesia intensity is high, additive is its fatal weakness, significantly limit its application; Though the latter, without additive but its analgesia intensity is weak, and has serious the intestines and stomach effect.Combunox is first is also a unique fixed dosage compound medicines be made up of opium analgesics oxycodone hydrochloride (OxycodoneHCl, 5mg) and NSAID (non-steroidal anti-inflammatory drug) (NSAID) ibuprofen (Ibuprofen, 400mg).Combunox is developed by Forest company, obtains FDA approval listing on November 26th, 2004, for most of wound or Post operation acute in the short-term process (within 7 days) of severe pain.Combunox single-dose, its analgesic effect be better than the oxycodone of low dosage or ibuprofen individually dosed, also than some other compound pain medicine better effects if.This medicine single or multiple drug tolerance is good, and short-period used can not produce the relevant serious adverse reaction of opioid drug or NSAID class medicine life-time service.This medicine is considered to acute, in severe pain effectively and select easily.
US4569937 and WO2004050025 patent all discloses oxycodone and directly mixes with adjuvant with ibuprofen, direct compression, or tabletting or encapsulated after wet granulation.US4569937 finds two medicine synergism, can reduce consumption and toxic and side effects.WO2004050025 as filler and fluidizer, substitutes microcrystalline Cellulose with silicified microcrystalline cellulose (particle diameter 1nm-100um), produces tissue adhesion effect, be beneficial to tabletting, but silicified microcrystalline cellulose price is abroad high, and cannot buy China is domestic, belong to that valency is high is not easy to obtain adjuvant.The coating powder that WO2004050025 also discloses coating is Opadry coating powder, but Opadry model is many, and not every Opadry coating powder is all suitable for the coating of ibuprofen oxycodone.Two sections of patents all do not report that oxycodone mixes with adjuvant with ibuprofen, the stability problem of preparation after tabletting.
Inventor is found by a large amount of experiments, in the common compound tablet preparation process of oxycodone hydrochloride and ibuprofen, oxycodone hydrochloride easily interacts with multiple binding agent, lubricant and produces degradation impurity, especially, when ibuprofen and oxycodone coexist, oxycodone hydrochloride degraded is more remarkable.
In the common compound tablet preparation process of oxycodone hydrochloride and ibuprofen, granulate after ibuprofen, oxycodone hydrochloride, binding agent mix with disintegrating agent, add fluidizer again, lubricant pressure conventional tablet, under room temperature and hot conditions, all can produce very large impurity, wherein the impurity content of high temperature is far above the upper limit of pharmacy quality control.
Causing impurity Producing reason to find, after ibuprofen mixes with oxycodone by our difference (1), then mixing with multiple disintegrating agent; (2) after ibuprofen being mixed with oxycodone, then mix with multiple binding agent; (3) after ibuprofen being mixed with oxycodone, then mix with multiple fluidizer; (4) after ibuprofen being mixed with oxycodone, then with multiple mix lubricant.Research all can produce very large impurity under there is room temperature and hot conditions after finding that ibuprofen mixes with binding agent with oxycodone hydrochloride, and wherein the impurity content of high temperature is far above the problem of the upper limit of pharmacy quality control.In multiple binding agent, when doing binding agent with polyvidone, the degraded of oxycodone hydrochloride is very serious, when coexisting with other binding agents, also there is degraded (see Table A) in various degree, when doing binding agent with hydroxypropyl emthylcellulose (HPMC), the degraded of oxycodone is minimum.And not having ibuprofen to deposit in case, between oxycodone hydrochloride and various binding agent, the compatibility has clear improvement, but when coexisting with domestic polyvidone k30, still has larger degraded (table B).
In the preparation process of the common compound tablet of ibuprofen oxycodone subsequently, we select the less HPMC(that to degrade with ibuprofen oxycodone to select different manufacturers, the HPMC of different batches), hydroxypropyl cellulose and sodium carboxymethyl cellulose be as binding agent, adopt conventional wet granulation technology, sample is placed in room temperature and hot conditions respectively, find different manufacturers, the HPMC of different batches is binding agent and two kinds of principal agent mixing wet granulations, the degraded still disunity of oxycodone hydrochloride, its quality uncontrollable (see table C).Doing binding agent with HPMC in addition, when making lubricant with magnesium stearate, sodium stearyl fumarate, the degraded of oxycodone has again obviously increases, and impurity content is far above the upper limit (table D) of pharmacy quality control.
Pharmaceutical preparation in preparation process, drug quality is controlled to be conducive to batch between diversity reduce, be conducive to reducing due to batch between the weak curative effect opposite sex that causes of difference.The degraded of pharmaceutical preparation principal agent in storage process in addition, meeting and then lessen the curative effect.In order to avoid the harmful effect that above-mentioned situation is brought, need to find a kind of solution oxycodone, ibuprofen and binding agent further, drug content degraded when lubricant coexists, and the uncontrollable method of quality.
Summary of the invention
The object of the invention is the above-mentioned deficiency for prior art, a kind of oxycodone hydrochloride and ibuprofen multilayer tablet are provided.
Another object of the present invention is to provide the preparation method of this oxycodone hydrochloride and ibuprofen multilayer tablet.
Object of the present invention realizes by following technical scheme:
A kind of ibuprofen and oxycodone multilayer tablet, wherein one deck is ibuprofen layer, is made up of ibuprofen and pharmaceutically acceptable adjuvant; Another layer is oxycodone layer, is made up of oxycodone and pharmaceutically acceptable adjuvant.
Described ibuprofen and oxycodone multilayer tablet are preferably three-layer tablet or double-layer tablet.
When described ibuprofen and oxycodone multilayer tablet are double-layer tablet, one deck is described ibuprofen layer, and another layer is described oxycodone layer.
When described ibuprofen and oxycodone multilayer tablet are three layers, intermediate layer is made up of the adjuvant not containing principal agent, and side, intermediate layer is described ibuprofen layer, and intermediate layer opposite side is described oxycodone layer.
Described ibuprofen layer does not contain principal agent oxycodone hydrochloride, containing ibuprofen, binding agent, disintegrating agent and lubricant; Described oxycodone layer does not contain principal agent ibuprofen, containing principal agent oxycodone hydrochloride, binding agent, disintegrating agent and lubricant.
Described ibuprofen layer preferably contains 80 ~ 800 parts by weight of ibuprofen, 5 ~ 200 part by weight of disintegrant, 1 ~ 100 parts by weight of binder; Described oxycodone layer preferably contains 1 ~ 20 weight portion oxycodone hydrochloride, 10 ~ 800 parts by weight of filler, 1 ~ 100 parts by weight of binder.
Described ibuprofen layer is further preferably containing 200 ~ 600 parts by weight of ibuprofen, 20 ~ 100 part by weight of disintegrant, 1 ~ 30 parts by weight of binder, described oxycodone layer is further preferably containing 2 ~ 10 weight portion oxycodone hydrochlorides, 30 ~ 400 parts by weight of filler, 1 ~ 30 parts by weight of binder.
Described intermediate layer comprises filler, binding agent, fluidizer and lubricant.
In described ibuprofen layer, disintegrating agent be selected from carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula and crystallite aluminum spraying dry thing, microcrystalline Cellulose, dried starch, pregelatinized starch or low-substituted hydroxypropyl cellulose one or more, binding agent is selected from hydroxypropyl emthylcellulose, polyvidone, hydroxypropyl cellulose, polyvinyl alcohol hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, ethyl cellulose, methylcellulose, ethylmethylcellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone-vinyl acetate co-polymer, starch, modified starch, carbomer, alginic acid, sodium alginate, calcium alginate, potassium alginate, ammonium alginate, xanthan gum, tragacanth, one or more in gelatin or arabic gum, in described oxycodone layer, filler is selected from mannitol, sorbitol, compressible sugar, sucrose, spherical sucrose, starch, pregelatinized starch, lactose, microcrystalline Cellulose, one or more in cellulose-lactose or dextrin, binding agent is selected from hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, ethyl cellulose, methylcellulose, ethylmethylcellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone-vinyl acetate co-polymer, starch, modified starch, carbomer, alginic acid, sodium alginate, calcium alginate, potassium alginate, ammonium alginate, xanthan gum, tragacanth, one or more in gelatin or arabic gum.
In described ibuprofen layer, disintegrating agent preferably from carboxymethyl starch sodium, polyvinylpolypyrrolidone or cross-linking sodium carboxymethyl cellulose, binding agent preferably from hydroxypropyl emthylcellulose, polyvidone or hydroxypropyl cellulose; In described oxycodone layer, filler is preferably from pregelatinized starch, lactose, microcrystalline Cellulose or cellulose-lactose, and binding agent is preferably from hydroxypropyl methylcellulose, hydroxypropyl cellulose or sodium carboxymethyl cellulose.The binding agent of oxycodone lamella can not select polyvidone.
Described multilayer tablet ibuprofen layer is also containing fluidizer and lubricant.
The preferred stearic acid of described lubricant, sodium stearyl fumarate, Pulvis Talci, Polyethylene Glycol etc.
The preferred silicon dioxide of described fluidizer, colloidality silicon dioxide, aluminium silicate etc.
A preparation method for ibuprofen of the present invention and oxycodone multilayer tablet, comprises the following steps:
(1), the preparation of ibuprofen granule:
Ibuprofen is mixed homogeneously with a part of disintegrating agent, adds binding agent under stirring, wet granular processed, granulate after dry; Add residue disintegrating agent, fluidizer and lubricant, mix homogeneously is for subsequent use;
(2) oxycodone hydrochloride granule:
Oxycodone hydrochloride is mixed homogeneously with filler, adds binding agent under stirring, wet granular processed, granulate after dry; Add fluidizer and lubricant, mix homogeneously is for subsequent use;
(3) preparation of ibuprofen oxycodone multilayer tablet:
By ibuprofen granule and oxycodone hydrochloride granule respectively as the charging aperture of the corresponding lamella of bi-layer tablet press tabletting, the double-deck plain sheet of oxycodone ibuprofen can be obtained; Or on the basis of step (1) and step (2), by filler, binding agent, fluidizer and lubricant are prepared into intermediate layer granulate, again by ibuprofen granule, intermediate layer granulate and oxycodone hydrochloride granule respectively as three laminate machine tablettings, ibuprofen and oxycodone three laminin sheet can be obtained;
Wherein, in every sheet, ibuprofen layer is containing ibuprofen 80 ~ 800 weight portion, disintegrating agent 5 ~ 200 weight portion, binding agent 1 ~ 100 weight portion; Oxycodone layer contains oxycodone 1 ~ 20 weight portion, filler 10 ~ 800 weight portion, binding agent 1 ~ 100 weight portion.
Multilamellar tablet machine generally uses in Chinese pharmaceutical enterprises, and the compacting of double-layer tablet and three-layer tablet is without the need to the equipment of stringent, and in pressing process, different lamella granules are placed in the charging aperture of corresponding lamella respectively, and compacting and ordinary tablet do not have difference, easily control.
In described ibuprofen layer, one or more preferably in carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula and crystallite aluminum spraying dry thing, microcrystalline Cellulose, dried starch, pregelatinized starch or low-substituted hydroxypropyl cellulose of disintegrating agent, binding agent is preferably from hydroxypropyl methylcellulose, polyvidone, hydroxypropyl cellulose, polyvinyl alcohol hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, ethyl cellulose, methylcellulose, ethylmethylcellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone-vinyl acetate co-polymer, starch, modified starch, carbomer, alginic acid, sodium alginate, calcium alginate, potassium alginate, ammonium alginate, xanthan gum, tragacanth, one or more in gelatin or arabic gum, in described oxycodone layer, filler is preferably from mannitol, sorbitol, compressible sugar, sucrose, spherical sucrose, starch, pregelatinized starch, lactose, microcrystalline Cellulose, one or more in cellulose-lactose or dextrin, binding agent is preferably from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, ethyl cellulose, methylcellulose, ethylmethylcellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone-vinyl acetate co-polymer, starch, modified starch, carbomer, alginic acid, sodium alginate, calcium alginate, potassium alginate, ammonium alginate, xanthan gum, tragacanth, one or more in gelatin or arabic gum.
In described ibuprofen layer, disintegrating agent is preferred from carboxymethyl starch sodium further, polyvinylpolypyrrolidone or cross-linking sodium carboxymethyl cellulose, and binding agent is preferred from hydroxypropyl methylcellulose further, polyvidone or hydroxypropyl cellulose; In described oxycodone layer, filler is excellent be selected from pregelatinized starch, lactose, microcrystalline Cellulose or cellulose-lactose further one or more, binding agent is preferred one or more in hydroxypropyl methylcellulose, hydroxypropyl cellulose or sodium carboxymethyl cellulose further.The binding agent of oxycodone lamella can not select polyvidone.
This preparation method also preferably includes multilayer tablet coating.
Described coating comprises: coating powder being dissolved in mass concentration is that the ethanol water of 10%-90% obtains coating solution, carries out coating to ibuprofen oxycodone multilamellar element sheet.
The preferred Opadry coating powder of described coating powder, further preferably Opadry coating powder Y-1-7000, Opadry coating powder OY-60901 or Opadry coating powder 03F-38033, the mass concentration of described ethanol water preferably 40% ~ 85%.
The present invention finds, selects the arbitrary model of Opadry coating powder, and when using conventional pure water solution or pure alcohol as coating solution, tablet surface has pit, and coating is uneven.When being the ethanol water of 10%-90% with the mass ratio of ethanol and water, preferably 40% ~ 85% time, with Opadry coating powder Y-1-7000, Opadry coating powder OY-60901, Opadry coating powder 03F-38033 coating, ibuprofen oxycodone multi-layer thin film coated tablet smooth surface is without pit, and coating effect is fine.
Beneficial effect:
Ibuprofen provided by the invention is in different lamellas respectively from oxycodone hydrochloride in oxycodone multilayer tablet and ibuprofen, and oxycodone and ibuprofen, under room temperature, high temperature, are not all degraded, the stability had and quality controllability.Avoid in common compound tablet, ibuprofen is deposited in case, and oxycodone and binding agent or oxycodone and binding agent, lubricant coexist, and the serious and uncontrollable problem of quality of principal agent degraded, is unfavorable for batch production.The adjuvant carboxymethyl starch sodium of the present invention's use in addition, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, polyvidone, hydroxypropyl cellulose, pregelatinized starch, lactose, microcrystalline Cellulose, cellulose-lactose and sodium carboxymethyl cellulose etc. belong to adjuvant cheap and easy to get in China.Avoid using price high and the silicified microcrystalline cellulose be not easy to obtain, also can play good tissue adhesion effect.
In addition, this law ethanol does coating solution with water quality than the ethanol water being 10%-90%, with Opadry coating powder Y-1-7000, Opadry coating powder OY-60901 or Opadry coating powder 03F-38033 coating, ibuprofen oxycodone film coated tablet smooth surface without pit, the coating effect had.
Detailed description of the invention
Embodiments of the invention are as described below, and described embodiment is used for exemplary illustration the present invention instead of limits the invention.
One, formulation stability is investigated
Embodiment 1
Containing 400mg ibuprofen, the preparation of the bilayer film garment piece (embodiment 1) of 5mg oxycodone hydrochloride, comprises the granule of preparation containing following compositions, uncoated tablets, film coated tablet.Below illustrate that the addition shown in bracket is illustrating prescription shown in embodiment 1.According to described preparation method, the preparing embodiment identical method can be adopted to be prepared of other double-layer tablet, difference is to need according to prescription different, and change addition, each Example formulations refers to table 1 ~ 3, table 5 ~ 6.
Preparation method:
The preparation of ibuprofen granule:
(1) adhesive solution (2% hydroxypropyl methylcellulose aqueous solution) is prepared
Hydroxypropyl methylcellulose (3g) is dissolved in (150g) in pure water as binding agent and obtains adhesive solution.
(2) ibuprofen granule is granulated
By ibuprofen (400g), pulverized 60 mesh sieves, it is for subsequent use that disintegrating agent carboxymethyl base Starch Sodium (15g) crosses 60 mesh sieves.Add ibuprofen, disintegrating agent carboxymethyl base Starch Sodium in high efficient mixed granulator successively, be dry mixed.Add appropriate 2% hydroxypropyl methylcellulose aqueous solution under stirring, granulate, cross 24 mesh sieve wet granulars, in 60 DEG C of baking ovens after drying, 24 mesh sieve granulate, obtain ibuprofen granule powder.Added the disintegrating agent carboxymethyl base Starch Sodium (30g) of 60 mesh sieves, silicon dioxide (4.8g) and stearic acid (2.4g), mix homogeneously, obtains ibuprofen granule for subsequent use.
Oxycodone hydrochloride granule
(3) adhesive solution (5% hydroxypropyl methylcellulose aqueous solution) is prepared
Hydroxypropyl methylcellulose (3g) is dissolved in (60g) in pure water as binding agent and obtains adhesive solution.
(4) oxycodone hydrochloride granule is granulated
By oxycodone hydrochloride (5g), pulverized 80 mesh sieves, it is for subsequent use that filler microcrystalline Cellulose (135g) crosses 60 mesh sieves.Oxycodone hydrochloride, filler microcrystalline Cellulose, is dry mixed 6min.Add appropriate 5% hydroxypropyl methylcellulose aqueous solution under stirring, high-shearing granulation, cross 24 mesh sieve wet granulars.In 60 DEG C of baking ovens after drying, 24 mesh sieve granulate, obtain oxycodone particle powder.Cross silicon dioxide (1.2g) and the stearic acid (0.6g) of 60 mesh sieves, mix homogeneously, obtains oxycodone hydrochloride granule for subsequent use.
(5) preparation of ibuprofen oxycodone double-layer tablet:
By ibuprofen granule and oxycodone hydrochloride granule respectively as the charging aperture of the corresponding lamella of rotary double-layer tablet machine, tabletting, can obtain the double-deck plain sheet of oxycodone ibuprofen.
(6) coating:
Add Opadry coating powder after taking ethanol water mixing, cross 80 mesh sieves after stirring 45min for subsequent use.Getting the double-deck plain sheet of ibuprofen oxycodone is placed in coating pan, and pot rotating speed is about 6r/min, and inlet temperature about 55 DEG C carries out coating, obtained ibuprofen oxycodone double-layer tablet.
Embodiment 2
Containing 400mg ibuprofen, the preparation of the three-layer thin-film garment piece (embodiment 2) of 5mg oxycodone, comprises the granule of preparation containing following compositions, uncoated tablets, film coated tablet.Below illustrate that the addition shown in bracket is illustrating prescription shown in embodiment 2.According to described preparation method, the preparing embodiment identical method can be adopted to be prepared of other three-layer tablet, difference is to need according to prescription different, and change addition, each Example formulations refers to table 1 ~ 3, table 5 ~ 6.
Preparation method:
The preparation of ibuprofen granule:
(1) adhesive solution (2% hydroxypropyl methylcellulose aqueous solution) is prepared
Hydroxypropyl emthylcellulose (3g) is dissolved in (150g) in pure water as binding agent and obtains adhesive solution.
(2) granulate
By ibuprofen (400g), pulverized 60 mesh sieves, it is for subsequent use that disintegrating agent carboxymethyl base Starch Sodium (15g) crosses 60 mesh sieves.Add ibuprofen, disintegrating agent carboxymethyl base Starch Sodium in high efficient mixed granulator successively, be dry mixed.Add appropriate 2% hydroxypropyl methylcellulose aqueous solution under stirring, granulate, cross 24 mesh sieve wet granulars, in 60 DEG C of baking ovens after drying, 24 mesh sieve granulate, obtain ibuprofen granule powder.Added the disintegrating agent carboxymethyl base Starch Sodium (30g) of 60 mesh sieves, silicon dioxide (4.8g) and stearic acid (2.4g), mix homogeneously, obtains ibuprofen granule for subsequent use.
Oxycodone hydrochloride granule
(3) adhesive solution (5% hydroxypropyl methylcellulose aqueous solution) is prepared
Hydroxypropyl emthylcellulose (3g) is dissolved in (60g) in pure water as binding agent and obtains adhesive solution.
(4) preparation of oxycodone granule
By oxycodone hydrochloride (5g), pulverized 80 mesh sieves, it is for subsequent use that filler microcrystalline Cellulose (135g) crosses 60 mesh sieves.Oxycodone hydrochloride, filler microcrystalline Cellulose, is dry mixed 6min.Add appropriate 5% hydroxypropyl methylcellulose aqueous solution under stirring, high-shearing granulation, cross 24 mesh sieve wet granulars.In 60 DEG C of baking ovens after drying, 24 mesh sieve granulate, obtain ibuprofen granule powder.Ibuprofen granule powder crosses silicon dioxide (1.2g) and the stearic acid (0.6g) of 60 mesh sieves, and mix homogeneously, obtains oxycodone hydrochloride granule for subsequent use.
(5) preparation of intermediate layer granulate:
Microcrystalline Cellulose (140g) is crossed 60 mesh sieves for subsequent use, add appropriate 5% hydroxypropyl methylcellulose aqueous solution under stirring, high-shearing granulation, cross 24 mesh sieve wet granulars.In 60 DEG C of baking ovens after drying, 24 mesh sieve granulate, added silicon dioxide (1.2g) and the stearic acid (0.6g) of 60 mesh sieves, mix homogeneously, obtains intermediate layer blank granules for subsequent use.
(6) preparation of ibuprofen oxycodone three-layer tablet:
By ibuprofen granule, intermediate layer granulate and oxycodone hydrochloride granule respectively as rotary three laminate machine tablettings, oxycodone ibuprofen three laminin sheet can be obtained.
(7) coating:
Add Opadry coating powder after taking ethanol water mixing, cross 80 mesh sieves after stirring 45min for subsequent use.Getting ibuprofen oxycodone three laminin sheet is placed in coating pan, and pot rotating speed is about 6r/min, and inlet temperature about 55 DEG C carries out coating, obtained ibuprofen oxycodone three-layer tablet.
In embodiment 1,3,5,7, prepared the bilayer tablet containing certain drug compositions, described double-layer tablet every sheet ibuprofen layer is respectively containing ibuprofen 400mg, 200mg, 600mg, 800mg, disintegrating agent, binding agent, every sheet oxycodone layer is respectively containing oxycodone hydrochloride 5mg, 2.5mg, 7.5mg, 10mg and filler and binding agent.
In embodiment 2,4,6,8, prepared the tri-layer tablets containing certain drug compositions, described three-layer tablet every sheet ibuprofen layer is respectively containing ibuprofen 400mg, 200mg, 600mg, 800mg, disintegrating agent, binding agent, every sheet oxycodone layer contains oxycodone hydrochloride 5mg respectively, 2.5mg, 7.5mg, 10mg and filler and binding agent, intermediate blank layer.
In comparative example 1,2 and 3, prepare the ibuprofen of every sheet respectively containing 400mg, 200mg and 600mg, and the oxycodone hydrochloride of 5mg, 2.5mg and 7.5mg,
Comparative example 1:
Containing 400mg ibuprofen, the preparation of the Film coated tablets (comparative example 1) of 5mg oxycodone hydrochloride, comprises granule, uncoated tablets, the film coating tablet of preparation containing following compositions.Below illustrate that the addition shown in bracket is illustrating prescription shown in comparative example 1.According to described preparation method, the preparing embodiment identical method can be adopted to be prepared of other sheet, difference is to need according to prescription different,
Change addition, each comparative example formula refers to table 4 ~ 6.
Preparation method:
The preparation of granule:
(1) adhesive solution (2% hydroxypropyl methylcellulose aqueous solution) is prepared
Hydroxypropyl methylcellulose (6g) is dissolved in (300g) in pure water as binding agent and obtains adhesive solution.
(2) granulate
By ibuprofen (400g), pulverized 60 mesh sieves, oxycodone hydrochloride (5g), pulverized 80 mesh sieves, carboxymethyl starch sodium (15g), and it is for subsequent use that microcrystalline Cellulose (135g) crosses 60 mesh sieves respectively.Add ibuprofen, oxycodone hydrochloride, carboxymethyl starch sodium successively in high efficient mixed granulator, microcrystalline Cellulose, be dry mixed.Add appropriate 2% hydroxypropyl methylcellulose aqueous solution under stirring, granulate, cross 24 mesh sieve wet granulars, in 60 DEG C of baking ovens after drying, 24 mesh sieve granulate.Added the carboxymethyl starch sodium (30g) of 60 mesh sieves, silicon dioxide (6g) and stearic acid (3g), mix homogeneously, obtains midbody particle for subsequent use.
(3) preparation of ibuprofen oxycodone sheet:
By granule as rotary tablet press, ibuprofen oxycodone element sheet can be obtained.
(4) coating:
Add Opadry coating powder after taking ethanol water mixing, cross 80 mesh sieves after stirring 45min for subsequent use.Getting ibuprofen oxycodone three laminin sheet is placed in coating pan, and pot rotating speed is about 6r/min, and inlet temperature about 55 DEG C carries out coating, obtained ibuprofen oxycodone sheet.
The prescription of particle powder in (a) embodiment 1 ~ 8 and comparative example 1 ~ 3
(1), the prescription of ibuprofen granule powder
Table 1 unit: g
(2), the prescription of oxycodone particle powder
Table 2 unit: g
(3), intermediate layer granulate prescription:
Table 3 unit: g
(4) comparative example's granule prescription:
Table 4 unit: g
B () is for the prescription of the granule/uncoated tablets of tabletting
Table 5 unit: g
The prescription of (c) coated tablet:
Table 6 unit: g
Effect example 1
Under room temperature 25 DEG C, high temperature 60 DEG C of conditions and in accelerated test (40 DEG C, the humidity of 75%), the preparation for preparation carries out influence factor's test, and evaluates its stability.Result shows, and the impurity content of double-layer tablet and three-layer tablet is significantly lower than the general thin garment piece of comparative example.Stability test data are in table 7
Table 7: stability test investigates data:
Stability test shows, and in room temperature 6 months and acceleration 3 months stability tests are investigated, the impurity content change of double-layer tablet and three-layer tablet is little, and degrade less, and the degraded of the ordinary tablet of matched group seriously, impurity degradation amount far exceedes the pharmaceutical analysis upper limit.
Two, adjuvant stability, controllability are investigated
In embodiment 1, 9, in 11, prepare the bilayer tablet containing certain drug compositions, described double-layer tablet every sheet ibuprofen layer is respectively containing ibuprofen 400mg, 200mg, 800mg, disintegrating agent, hydroxypropyl emthylcellulose, Huzhou is wherein used to look forward to the hydroxypropyl emthylcellulose of 20091201 batches in embodiment 1, embodiment 9 uses Huzhou to look forward to the hydroxypropyl emthylcellulose of 20111101 batches, embodiment 11 uses Huzhou to look forward to the hydroxypropyl emthylcellulose of 20100901 batches, every sheet oxycodone layer is respectively containing oxycodone hydrochloride 5mg, 2.5mg, 7.5mg, 10mg and filler and hydroxypropyl emthylcellulose.Formula is in table 8 ~ 10, table 12 ~ 13.
In embodiment 2, 10, in 12, prepare the tri-layer tablets containing certain drug compositions, described three-layer tablet every sheet ibuprofen layer is respectively containing ibuprofen 400mg, 200mg, 800mg, disintegrating agent, hydroxypropyl emthylcellulose, Huzhou is wherein used to look forward to the hydroxypropyl emthylcellulose of 20091201 batches in embodiment 2, embodiment 10 uses Huzhou to look forward to the hydroxypropyl emthylcellulose of 20111101 batches, embodiment 12 uses Huzhou to look forward to the hydroxypropyl emthylcellulose of 20100901 batches, every sheet oxycodone layer is respectively containing oxycodone hydrochloride 5mg, 2.5mg, 10mg and filler and hydroxypropyl emthylcellulose, intermediate blank layer.Formula is in table 8 ~ 10, table 12 ~ 13.
In comparative example 1,4 and 5, prepare the ibuprofen of every sheet respectively containing 400mg, 200mg and 800mg, with the oxycodone of 5mg, 2.5mg and 10mg, Huzhou is used to look forward to the hydroxypropyl emthylcellulose of 20091201 batches in comparative example 1, comparative example 4 uses Huzhou to look forward to the hydroxypropyl emthylcellulose of 20111101 batches, and comparative example 5 uses Huzhou to look forward to the hydroxypropyl emthylcellulose of 20100901 batches.Formula is in table 10 ~ 13.
The prescription of (a) particle powder
(1), the prescription of ibuprofen granule powder
Table 8 unit: g
(2), the prescription of oxycodone particle powder
Table 9 unit: g
(3), intermediate layer granulate prescription:
Table 10 unit: g
(4) comparative example's granule
Table 11 unit: g
B () is for the prescription of the granule/uncoated tablets of tabletting
Table 12 unit: g
The prescription of (c) coated tablet
Table 13 unit: g
Effect example 2
Under room temperature 25 DEG C, high temperature 60 DEG C of conditions and in accelerated test (40 DEG C, the humidity of 75%), the preparation for preparation carries out influence factor's test, and evaluates use hydroxypropyl emthylcellulose as binding agent, the stability of multilayer tablet and quality controllability.Result shows, and the impurity content of double-layer tablet and three-layer tablet is significantly lower than the general thin garment piece of comparative example, and quality controllability is better than comparative example, in table 14.
Table 14: stability, steering test investigate data
Comparative example 6
After ibuprofen mixes with oxycodone hydrochloride by (1) respectively, then mix with multiple disintegrating agent; (2) after ibuprofen being mixed with oxycodone hydrochloride, then mix with multiple binding agent; (3) after ibuprofen being mixed with oxycodone, then mix with multiple fluidizer; (4) after ibuprofen being mixed with oxycodone, then with multiple mix lubricant.In room temperature and high temperature (60 DEG C) the single impurity of 5 days and total impurities situation.Impurity listed in Table A is except the impurity of API is the solvent impurity brought in raw material, and remaining sample impurity is the solvent impurity brought in the raw material of minute quantity, and oxycodone hydrochloride impurity.Wherein in Table A, continuing of conforming to quality requirements of room temperature 5 days and high temperature 5 days impurity is cooked room temperature 6 months stability tests.Test display, after API mixes with binding agent, all can produce very large impurity under there is room temperature and hot conditions, and wherein the impurity content of high temperature is far above the problem of the upper limit of pharmacy quality control.In multiple binding agent, when doing binding agent with polyvidone, the degraded of oxycodone hydrochloride is very serious, when coexisting with other binding agents, also there is degraded in various degree.But the hydroxypropyl emthylcellulose in API and binding agent room temperature and the high temperature impurity degradation of 5 days less.API and lubricant can meet pharmacy quality research requirement for 5 days at room temperature and high temperature in addition.
Table A: (API is ibuprofen+oxycodone hydrochloride mixture)
Comparative example 7
Oxycodone hydrochloride is mixed with domestic conventional various binding agents respectively, investigates room temperature and high temperature (60 degree) the single impurity of 5 days and total impurities situation, the results are shown in Table B.In table B, listed impurity is oxycodone hydrochloride impurity.Result shows, and when not having ibuprofen to deposit in case, between oxycodone hydrochloride and various binding agent, the compatibility has clear improvement.When doing binding agent with HPMC, the degraded of oxycodone is minimum.But when coexisting with domestic polyvidone k30, still have larger degraded.
Table B
Comparative example 8
Adopt conventional wet granulation technology, adopt different binding agent to granulate after directly being mixed with adjuvant by two kinds of principal agents (ibuprofen and oxycodone hydrochloride), sample is placed in room temperature respectively and hot conditions investigates magazine situation, the results are shown in Table C.In table C, listed impurity is oxycodone hydrochloride impurity.We can find, adopt the technique of two kinds of common principal agent mixing wet granulations, take HPMC as binding agent, and oxycodone hydrochloride impurity under the high temperature conditions increases minimum.But different manufacturers, the HPMC of different batches is binding agent and two kinds of principal agent mixing wet granulations, and the degraded still disunity of oxycodone hydrochloride, its quality is uncontrollable.
The adjuvant of pharmacy quality research requirement and room temperature within 5 days, can be met for room temperature 5 days and high temperature and within 5 days, meet pharmacy quality research and high temperature 5 days ungratified adjuvants, do room temperature 6 months stability tests further, the Particle Phase of the HPMC of 20091201 batches of test display Huzhou prospect is minimum to degraded, a little higher than study of pharmacy quality control requirement of degradation impurity.
Table C
Comparative example 9
We choose in table and degrade ibuprofen oxycodone granule minimum (Huzhou HPMC of looking forward to 20091201 batches does the granule of binding agent), with lubricant, fluidizer is tabletting together, in room temperature and high temperature (60 degree) the single impurity of 5 days and total impurities situation, the results are shown in Table D, in table D, listed impurity is oxycodone hydrochloride impurity.Result shows different lubricants, different to the stability influence of granule.The adjuvant of pharmacy quality research requirement and room temperature within 5 days, can be met for room temperature 5 days and high temperature and within 5 days, meet pharmacy quality research and high temperature 5 days ungratified adjuvants, the accelerated test of do room temperature further 6 months and 3 months, result display silicon dioxide, stearic acid do the requirement that lubricant and its room temperature of fluidizer degradation impurity of 5 days meet pharmacy quality research, but the test of its ordinary temperature stability of 6 months and the accelerated test of 3 months, its degradation impurity still can not meet the requirement of pharmacy quality research.
Table D
In present specification, hydroxypropyl emthylcellulose has another name called hydroxypropyl methylcellulose, english abbreviation HPMC.
Claims (16)
1. ibuprofen and an oxycodone multilayer tablet, is characterized in that wherein one deck is ibuprofen layer, is made up of ibuprofen and pharmaceutically acceptable adjuvant; Another layer is oxycodone layer, is made up of oxycodone and pharmaceutically acceptable adjuvant.
2. multilayer tablet according to claim 1, is characterized in that described ibuprofen and oxycodone multilayer tablet are three-layer tablet or double-layer tablet.
3. multilayer tablet according to claim 2, when it is characterized in that described ibuprofen and oxycodone multilayer tablet are double-layer tablet, one deck is described ibuprofen layer, and another layer is described oxycodone layer.
4. multilayer tablet according to claim 2, when it is characterized in that described ibuprofen and oxycodone multilayer tablet are three-layer tablet, intermediate layer is made up of the adjuvant not containing principal agent, and side, intermediate layer is described ibuprofen layer, and intermediate layer opposite side is described oxycodone layer.
5. the multilayer tablet according to any one of Claims 1 to 4, is characterized in that described ibuprofen layer not containing principal agent oxycodone hydrochloride, containing ibuprofen, binding agent, disintegrating agent and lubricant; Described oxycodone layer does not contain principal agent ibuprofen, containing principal agent oxycodone hydrochloride, binding agent, disintegrating agent and lubricant.
6. multilayer tablet according to claim 5, is characterized in that described ibuprofen layer contains 80 ~ 800 parts by weight of ibuprofen, 5 ~ 200 part by weight of disintegrant, 1 ~ 100 parts by weight of binder; Described oxycodone layer contains 1 ~ 20 weight portion oxycodone hydrochloride, 10 ~ 800 parts by weight of filler, 1 ~ 100 parts by weight of binder.
7. multilayer tablet according to claim 6, it is characterized in that described ibuprofen layer contains 200 ~ 600 parts by weight of ibuprofen, 20 ~ 100 part by weight of disintegrant, 1 ~ 30 parts by weight of binder, described oxycodone layer contains 2 ~ 10 weight portion oxycodone hydrochlorides, 30 ~ 400 parts by weight of filler, 1 ~ 30 parts by weight of binder.
8. multilayer tablet according to claim 4, is characterized in that described intermediate layer comprises filler, binding agent, fluidizer and lubricant.
9. multilayer tablet according to claim 5, it is characterized in that in described ibuprofen layer, disintegrating agent be selected from carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula and crystallite aluminum spraying dry thing, microcrystalline Cellulose, dried starch, pregelatinized starch or low-substituted hydroxypropyl cellulose one or more, binding agent is selected from hydroxypropyl emthylcellulose, polyvidone, hydroxypropyl cellulose, polyvinyl alcohol hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, ethyl cellulose, methylcellulose, ethylmethylcellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone-vinyl acetate co-polymer, starch, modified starch, carbomer, alginic acid, sodium alginate, calcium alginate, potassium alginate, ammonium alginate, xanthan gum, tragacanth, one or more in gelatin or arabic gum, in described oxycodone layer, filler is selected from mannitol, sorbitol, compressible sugar, sucrose, spherical sucrose, starch, pregelatinized starch, lactose, microcrystalline Cellulose, one or more in cellulose-lactose or dextrin, binding agent is selected from hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, ethyl cellulose, methylcellulose, ethylmethylcellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone-vinyl acetate co-polymer, starch, modified starch, carbomer, alginic acid, sodium alginate, calcium alginate, potassium alginate, ammonium alginate, xanthan gum, tragacanth, one or more in gelatin or arabic gum.
10. multilayer tablet according to claim 9, it is characterized in that in described ibuprofen layer, disintegrating agent is selected from carboxymethyl starch sodium, polyvinylpolypyrrolidone or cross-linking sodium carboxymethyl cellulose, binding agent is selected from hydroxypropyl emthylcellulose, polyvidone or hydroxypropyl cellulose; In described oxycodone layer, filler is selected from pregelatinized starch, lactose, microcrystalline Cellulose or cellulose-lactose, and binding agent is selected from hydroxypropyl emthylcellulose, hydroxypropyl cellulose or sodium carboxymethyl cellulose.
11., according to the arbitrary described multilayer tablet of claim 7 ~ 9, is characterized in that described ibuprofen layer and oxycodone layer all also containing fluidizer and lubricant, preferred silicon dioxide and stearic acid.
The preparation method of 12. 1 kinds of ibuprofen according to claim 1 and oxycodone multilayer tablet, is characterized in that, comprise the following steps:
(1) preparation of ibuprofen granule:
Ibuprofen is mixed homogeneously with a part of disintegrating agent, adds binding agent under stirring, wet granular processed, granulate after dry; Add residue disintegrating agent, fluidizer and lubricant, mix homogeneously is for subsequent use;
(2) oxycodone hydrochloride granule:
Oxycodone hydrochloride is mixed homogeneously with filler, adds binding agent under stirring, wet granular processed, granulate after dry; Add fluidizer and lubricant, mix homogeneously is for subsequent use;
(3) preparation of ibuprofen oxycodone multilayer tablet:
Ibuprofen granule and oxycodone granule are placed in bi-layer tablet press tabletting respectively, the double-deck plain sheet of ibuprofen oxycodone can be obtained; Or on the basis of step (1) and step (2), by filler, binding agent, fluidizer and mix lubricant are prepared into intermediate layer granulate, again by described ibuprofen granule, intermediate layer granulate and described oxycodone hydrochloride granule respectively as three laminate machine tablettings, ibuprofen oxycodone three laminin sheet can be obtained;
Wherein, in every sheet, ibuprofen layer is containing ibuprofen 80 ~ 800 weight portion, disintegrating agent 5 ~ 200 weight portion, binding agent 1 ~ 100 weight portion; Oxycodone layer contains oxycodone 1 ~ 20 weight portion, filler 10 ~ 800 weight portion, binding agent 1 ~ 100 weight portion.
13. multilayer tablets according to claim 12, it is characterized in that, in described ibuprofen layer, disintegrating agent is carboxymethyl starch sodium, polyvinylpolypyrrolidone or cross-linking sodium carboxymethyl cellulose, binding agent is hydroxypropyl emthylcellulose, polyvidone or hydroxypropyl cellulose; In described oxycodone layer, filler is pregelatinized starch, lactose, microcrystalline Cellulose or cellulose-lactose, and binding agent is hydroxypropyl emthylcellulose, hydroxypropyl cellulose or sodium carboxymethyl cellulose.
14. preparation methoies according to claim 12 or 13, is characterized in that this preparation method also comprises multilayer tablet coating.
15. preparation methoies according to claim 14, is characterized in that described multilayer tablet coating comprises: coating powder being dissolved in mass concentration is that the ethanol water of 10%-90% obtains coating solution, carry out coating to ibuprofen oxycodone multilamellar element sheet.
16. preparation methoies according to claim 15, is characterized in that described coating powder is Opadry coating powder, preferred Opadry coating powder Y-1-7000, Opadry coating powder OY-60901 or Opadry coating powder 03F-38033; The mass concentration of described ethanol water is 40% ~ 85%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004050025A2 (en) * | 2002-11-29 | 2004-06-17 | Forest Laboratories, Inc. | Combination of ibuprofen and oxycodone for acute pain relief |
| US20080175897A1 (en) * | 2006-03-06 | 2008-07-24 | Pozen Inc. | Dosage forms for administering combinations of drugs |
| CN101410095A (en) * | 2006-03-06 | 2009-04-15 | 波曾公司 | Dosage forms for administering combinations of drugs |
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2013
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004050025A2 (en) * | 2002-11-29 | 2004-06-17 | Forest Laboratories, Inc. | Combination of ibuprofen and oxycodone for acute pain relief |
| US20080175897A1 (en) * | 2006-03-06 | 2008-07-24 | Pozen Inc. | Dosage forms for administering combinations of drugs |
| CN101410095A (en) * | 2006-03-06 | 2009-04-15 | 波曾公司 | Dosage forms for administering combinations of drugs |
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Address after: 221004 No. 18 Yang Shan Road, Xuzhou Economic Development Zone, Xuzhou, Jiangsu Applicant after: Jiangsu Nhwa Pharmaceutical Co., Ltd. Address before: 221007 Zhongshan North Road, Jiangsu, No. 289, Applicant before: Jiangsu Nhwa Pharmaceutical Co., Ltd. |
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Application publication date: 20150325 |