CN103169728A - Anti-AIDS (Acquired Immune Deficiency Syndrome) compound preparation and preparation method thereof - Google Patents
Anti-AIDS (Acquired Immune Deficiency Syndrome) compound preparation and preparation method thereof Download PDFInfo
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- CN103169728A CN103169728A CN 201110442503 CN201110442503A CN103169728A CN 103169728 A CN103169728 A CN 103169728A CN 201110442503 CN201110442503 CN 201110442503 CN 201110442503 A CN201110442503 A CN 201110442503A CN 103169728 A CN103169728 A CN 103169728A
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Abstract
The invention discloses an anti-AIDS (Acquired Immune Deficiency Syndrome) compound preparation and a preparation method thereof. In particular, the compound preparation comprises 1) safe zidovudine in effective amount for treatment or pharmaceutically acceptable derivatives; 2) safe lamivudine in effective amount for treatment or pharmaceutically acceptable derivatives; 3) safe nevirapine in effective amount for treatment or pharmaceutically acceptable derivatives; 4) a disintegrating agent; and 5) pharmaceutically acceptable carriers or auxiliary materials beside the disintegrating agent, wherein the content of the disintegrating agent is 4-15wt% of total weight the compound preparation. The compound preparation is quick to disintegrate and adequate to dissolve. The invention further discloses a method for preparing the compound preparation.
Description
Technical field
The invention belongs to field of medicaments, particularly, relate to anti-AIDS compound preparation and preparation method thereof, more specifically, relate to compound preparation that comprises zidovudine, lamivudine and nevirapine and preparation method thereof.
Background technology
Acquired immune deficiency syndrome (AIDS) is walked crosswise and is wreaked havoc in the whole world, and the mankind's healthy and existence in serious threat, individual, community and country has all been produced destructive impact.China is since 1985 find the first AIDS, and the HIV number of the infected constantly rises.Especially occur high popular in some areas and specific crowd.Whole nation patients infected hiv number of reports sharply rises, and the epidemic situation numeral increases obviously, and the Mortality number continues to increase, and the Female-cases ratio rises.By in by the end of October, 2010, accumulative total is reported patients infected hiv and patient's more than 370,000 examples, and wherein patient more than 130,000 is routine, dead more than 6.8 ten thousand examples.
One of subject matter in anti-AIDS treatment is the generation of drug resistance variant.Single therapy generally needs long-term treatment, easily causes the HIV virus mutation and produces HIV drug resistance variant, increases adverse reaction rate.Highly active antiretroviral therapy (Highly Active Antiretroviral Therapy, HARRT claim again " HAART ") is the effective treating AIDS scheme of acknowledged in the world at present.At present the most frequently used is the administering drug combinations scheme of two kinds of efabirenzs and non-nucleoside reverse transcriptase inhibitor or protease inhibitor.Such composite reagent can be used for acute or chronic HIV the infected, or the AIDS patient of different stadium.The application of scheme of combination drug therapy can reduce the generation of HIV drug resistance strain, even can suppress copying of HIV virus within the time that is enough to eliminate HIV in body.But HIV infects with the scheme of combination drug therapy treatment, patient's non-compliance is a serious problem, patient's daily requirement is taken many different medicines (maximum takes 27 (sheet) medicines day by day), this non-compliance need the correct time interval to take medicine and be careful in one's diet, because may cause producing HIV multiple drug resistance toxicity.Therefore be necessary very much to develop compound preparation.
At present, although the compound preparation of zidovudine, lamivudine and nevirapine is disclosed,, existing preparation technology exists a lot of defectives, comprise complex process, operation easier is high, dissolution is low, dissolution rate slow (standard that even can not meet FDA) etc.
For example use and mix disintegrating agent (mixing that is different types of disintegrating agent is used), increased operation easier, make tablet technique relative complex, and the disintegrating agent consumption is very low, make In Vitro Dissolution partially slow, affect interior absorption of body of medicine.(as WO2006/001029, in addition, in the prior art, also use the higher lubricant quantity such as magnesium stearate easily to cause tablet to be difficult to the hardness that reaches higher, thereby make the tablet friability to have problems, also may slow down the disintegration of tablet time simultaneously, affect interior absorption of body of medicine.)
Adopt for another example respectively zidovudine and lamivudine are mixed rear wet granulation with filler, disintegrating agent; and wet granulation after nevirapine is mixed with filler, disintegrating agent; and then two kinds of granules are mixed, add tabletting after the disintegrating agent that adds, fluidizer, mix lubricant.Described technique is comparatively complicated.(as WO2006/114709, result show zidovudine and lamivudine in the time of 15 minutes In Vitro Dissolution all greater than 85%, and nevirapine in the time of 30 minutes less than 85%, do not reach FDA to the dissolution formulation stripping 30 minutes domestic demands greater than 85% limit.)
Therefore, be necessary very to develop that a kind of method for making is easy, each active component dissolution rate is high and the compound preparation of the sufficient anti-AIDS of stripping.
Summary of the invention
One of purpose of the present invention is to provide the compound preparation of the high and sufficient anti-AIDS of stripping of a kind of each active component dissolution rate.
Another object of the present invention is to provide a kind of easy and simple to handle, the compound preparation preparation method of the simple anti-AIDS of technique.
First aspect present invention provides a kind of anti-AIDS compound preparation, comprises:
1) zidovudine or its pharmaceutically acceptable derivates of safety and treatment effective dose;
2) lamivudine or its pharmaceutically acceptable derivates of safety and treatment effective dose;
3) nevirapine or its pharmaceutically acceptable derivates of safety and treatment effective dose;
4) disintegrating agent;
5) pharmaceutically acceptable carrier or the adjuvant except disintegrating agent;
Wherein, the content of described disintegrating agent is the 4-15wt% of compound preparation gross weight.
In another preference, described compound preparation is solid dosage forms.
In another preference, described compound preparation has following dissolution characteristic: the dissolution of 30 minutes is greater than 85% in the 0.1N hydrochloric acid solution.
In another preference, described compound preparation has following dissolution characteristic: the dissolution of 30 minutes is greater than 90%, more preferably greater than 94% in the 0.1N hydrochloric acid solution.
In another preference, described disintegrating agent is selected from lower group: modified starch, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpolypyrrolidone or its combination.
In another preference, the content of described disintegrating agent is the 4.5-15wt% of compound preparation gross weight, preferably, is 5-10wt%.
In another preference, described compound preparation comprises: tablet, capsule, granule or pill.
In another preference, described adjuvant is selected from lower group: filler, binding agent, lubricant, coloring agent, correctives or its combination.
In another preference, described filler is selected from lower group: starch, lactose, mannitol, Icing Sugar, microcrystalline Cellulose, pregelatinized Starch or its combination; And/or
Described binding agent is selected from lower group: starch slurry, polyvinylpyrrolidone (PVP), hypromellose (HPMC), hyprolose (HPC) or its combination; And/or
Described lubricant is selected from lower group: magnesium stearate, Pulvis Talci, micropowder silica gel or its combination.
In another preference, for the compound preparation gross weight, the content of described lubricant is 0.2-1wt%, is preferably 0.5-0.8wt%.
In another preference, for the compound preparation gross weight, the content of described filler is 5-20wt%, is preferably 10-15wt%.
In another preference, for the compound preparation gross weight, the content of described zidovudine is 20-50wt%, and the content of described lamivudine is 10-30wt%, and the content of described nevirapine is 15-35wt%.
In another preference, for the compound preparation gross weight, the content of described zidovudine is 30-40wt%, and the content of described lamivudine is 15-25wt%, and the content of described nevirapine is 20-30wt%.
In another preference, for the compound preparation gross weight, the content of described zidovudine is 33-40wt%, and the content of described lamivudine is 15-20wt%, and the content of described nevirapine is 22-28wt%.
In another preference, in described compound preparation, the per unit dosage form comprises 100～450mg zidovudine, 50～200mg lamivudine and 50～300mg nevirapine.
In another preference, in described compound preparation, the per unit dosage form comprises 300mg zidovudine, 150mg lamivudine and 200mg nevirapine.
In another preference, in described compound preparation, the per unit dosage form comprises 150mg zidovudine, 75mg lamivudine and 100mg nevirapine.
In another preference, compound preparation of the present invention is to prepare with the method described in second aspect present invention.
Second aspect present invention provides a kind of preparation method of anti-AIDS compound preparation, comprises step:
A) with zidovudine, lamivudine, nevirapine and in add adjuvant and carry out pretreatment, wherein, add adjuvant in described and comprise disintegrating agent and optional filler;
B) with pretreated zidovudine, lamivudine, nevirapine and in add adjuvant and mix after, obtain mixed material, and mixed material carried out wet granulation, thereby obtain material through granulating;
C) material through granulating that step b is obtained and add adjuvant and mix after, carry out tabletting or capsule-filling and process, thereby obtain anti-AIDS compound tablet or capsule;
Wherein, the described adjuvant that adds comprises lubricant, optional disintegrating agent and optional filler.
In another preference, adding adjuvant in described is disintegrating agent and filler;
In another preference, the described adjuvant that adds is lubricant and disintegrating agent.
In another preference, the described adjuvant that adds is lubricant.
In another preference, the described adjuvant that adds is lubricant and filler.
In another preference, described pretreatment comprises: pulverize and sieve.
In another preference, in described step b, wet granulation comprises: mixed material is mixed with binding agent, then granulate, wherein said binding agent is selected from lower group: starch slurry, polyvinylpyrrolidone, hypromellose, hyprolose or its combination.
In another preference, the wet granulation in described step b is to adopt high shear to stir to granulate or fluidized bed granulation.
In another preference, described step b also comprises: the material of granulating is carried out drying, thereby obtain drying, the material through granulating, wherein, described drying mode adopts carriage-type drying or fluid bed drying.
In another preference, described step b also comprises: the material through granulating is ground and granulate is processed, thereby obtain through grinding and the material of granulate.
In another preference, the weight ratio of the first active component zidovudine, the second active component lamivudine, the 3rd active component nevirapine and Nei Jia adjuvant is 20-50: 10-30: 15-35: 10-25.
In another preference, in to add adjuvant be 1: 5 to 60: 1 with the weight ratio that adds adjuvant, be preferably 1: 1 to 50: 1, be more preferably 2: 1 to 40: 1, be 3: 1 to 30: 1 best.
In another preference, described preparation method comprises step:
1) with zidovudine, lamivudine, nevirapine and in add the adjuvant pretreatment of sieving;
2) take the pretreated zidovudine of 20-50wt%, the pretreated lamivudine of 10-30wt%, the pretreated nevirapine of 15-35wt% and 10-25wt% and add adjuvant in pretreated, after putting the middle mixing of wet granulator (or blender), add binding agent, then carry out wet granulation, thereby obtain the material through granulating;
3) with the material of step 2 gained in 40-80 ℃ of drying, thereby obtain the material of drying;
4) material with step 3 gained grinds and the granulate processing, thereby obtains the material through grinding and granulate;
5) add in the material of step 4 gained and add adjuvant, be placed in blender and mix, thereby obtain containing the material that adds adjuvant;
6) material with step 5 gained carries out tabletting and Cotton seeds, thereby obtains the anti-AIDS compound tablet;
Wherein above-mentioned percentage ratio is pressed the total restatement of compound preparation.
In another preference, described preparation method, described step 6 is processed for step 5 gained material being carried out capsule charge, thereby obtains the anti-AIDS compound capsule.
Third aspect present invention provides a kind of blend (blend), and described blend is made of following component:
The first active component: zidovudine or its pharmaceutically acceptable derivates;
The second active component: lamivudine or its pharmaceutically acceptable derivates;
The 3rd active component: nevirapine or its pharmaceutically acceptable derivates; With
Disintegrating agent and optional filler;
And described blend is to form by described the first active component, the second active component, the 3rd active component and disintegrating agent and optional filler are mixed together.
In another preference, the weight ratio of the first active component, the second active component, the 3rd active component and disintegrating agent and optional filler (adding adjuvant namely) is 20-50: 10-30: 15-35: 10-25.
When adding adjuvant in of the present invention and comprising filler, the weight ratio of disintegrating agent and filler is generally 10: 90 to 90: 10, is preferably 12: 88 to 30: 70, is more preferably 15: 85 to 40: 60.
In another preference, by the interior total weight that adds adjuvant, in the disintegrating agent that adds in adjuvant generally account for 10-60wt%, be preferably 15-40wt%.
In another preference, the disintegrating agent in described blend is the disintegrating agent of single kind.
Fourth aspect present invention provides a kind of compound preparation, and described compound preparation contains the described blend of third aspect present invention and pharmaceutically acceptable carrier.
In another preference, the disintegrating agent in the disintegrating agent in described blend and described pharmaceutically acceptable carrier is the disintegrating agent of identical type.
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can making up mutually between specifically described each technical characterictic in below (eg embodiment), thus consist of new or preferred technical scheme.As space is limited, this tired stating no longer one by one.
The specific embodiment
The inventor is by long-term and deep research, be surprised to find that, for having developed the compound preparation that contains zidovudine, lamivudine, nevirapine, by with the disintegrating agent of three kinds of active component and high-load (comprise high-load in disintegrating agent and the optional disintegrating agent that adds) the formed mixture of blend, carry out pelletize with wet method, can make easily the compound preparation of the high and sufficient anti-AIDS of stripping of active component dissolution rate.Experiment shows, compound preparation of the present invention has the dissolution rate that significantly improves (30 minutes far above 85%).On this basis, the inventor has completed the present invention.
Term
As used herein, term " active component " refers to zidovudine or its pharmaceutically acceptable derivates, lamivudine or its pharmaceutically acceptable derivates, and nevirapine or its pharmaceutically acceptable derivates.
As used herein, term " pharmaceutically acceptable derivates " refers to any pharmaceutically acceptable salt, hydrate, solvate, fat (or ester) or its salt or to receiver's medication the time, can provide any other compound of (directly or indirectly) desired active component or its any active metabolite or residue.
As used herein, term " pharmaceutically acceptable salt " refers to the formed salt that is suitable as medicine of active component of the present invention and acid or alkali.Pharmaceutically acceptable salt comprises inorganic salt and organic salt.The one preferred salt of class is active component of the present invention and the sour salt that forms.The acid that is fit to formation salt includes, but are not limited to: the mineral acids such as hydrochloric acid, hydrobromic acid, Fluohydric acid., sulphuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propanoic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acid such as benzenesulfonic acid; And the acidic amino acid such as aspartic acid, glutamic acid.
Zidovudine (Zidovudine)
Claim again AZT; AZT; Or 3 '-nitrine-3 '-deoxidation breast glycoside.Chemistry 1-(3-nitrine-2,3-dideoxy-β-D-RIBOSE) by name-5-methylpyrimidine-2,4 (1H, 3H)-diketone.Molecular formula is C
10H
13N
5O
4, molecular weight is 267.24.As anti-AIDS and antiviral agents.Be used for the treatment that acquired immune deficiency syndrome (AIDS) or the syndrome patient relevant with acquired immune deficiency syndrome (AIDS) and immunodeficiency virus (HIV) infect.
Lamivudine (Lamivudine)
Claim again (2R-cis)-4-amino-1-(2-methylol-1,3-oxygen sulfur Polymorphs-5-yl)-1H-pyrimid-2-one, for white crystals or crystalline powder chemical formula are C
8H
11N
3O
3S, molecular weight are 229.25.Lamivudine is nucleoside analog, and antiviral drugs is to the synthetic of viral DNA chain with extend competitive inhibitory action.
Nevirapine (nevirapine)
Chemical name is 11-cyclopropyl-5,11-dihydro-4-methyl-6 hydrogen-two pyridines-[3,2-b:2,3-e] [Isosorbide-5-Nitrae] diazepine-6-ketone, and molecular formula is C
15H
14N
4O, molecular weight are 266.3.Nevirapine is the sweet class reverse transcriptase inhibitors of the non-core of HIV-1 (Non-Nucleoside Reverse Transcriptase Inhibitor, NNRTI).Nevirapine directly is connected with the reverse transcriptase of HIV-1 and breaks to block by the catalysis end that makes this enzyme the DNA polymerase activity that RNA relies on and DNA relies on.
Compound preparation
Compound preparation of the present invention comprises zidovudine or its pharmaceutically acceptable derivates, lamivudine or its pharmaceutically acceptable derivates and nevirapine or its pharmaceutically acceptable derivates in safety and treatment effective dose scope, disintegrating agent and other pharmaceutically acceptable excipient or the carrier except disintegrating agent.
A kind of preferred compound preparation of the present invention comprises blend of the present invention and pharmaceutically acceptable excipient or carrier, and wherein said blend is made of following component:
The first active component: zidovudine or its pharmaceutically acceptable derivates;
The second active component: lamivudine or its pharmaceutically acceptable derivates;
The 3rd active component: nevirapine or its pharmaceutically acceptable derivates; With
Disintegrating agent and optional filler.
As used herein, term " safety and treatment effective dose " refers to: the amount of active component is enough to obviously improve the state of an illness, and is unlikely to produce serious side effect.Usually, compound preparation contains 1-2000mg active component/agent of the present invention, more preferably, contains 10-450mg active component/agent of the present invention.Preferably, described " potion " is a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more compatibility solids or liquid filler or gelatinous mass, they are suitable for the people uses, and enough purity and enough low toxicity must be arranged." compatibility " referred to herein as each component energy and active component of the present invention and blending mutually between them in compound preparation, and the drug effect of not obvious reduction active component.
Pharmaceutically acceptable carrier part example has cellulose and derivant (as sodium carboxymethyl cellulose, ethyl cellulose sodium, cellulose ethanoate etc.) thereof, gelatin, Talcum, kollag (as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (as Oleum Glycines, Oleum sesami, Oleum Arachidis hypogaeae semen, Fructus Canarii albi wet goods), polyhydric alcohol (as propylene glycol, glycerol, mannitol, sorbitol etc.), emulsifying agent (as tween
), wetting agent (as sodium lauryl sulphate), coloring agent, flavoring agent, stabilizing agent, antioxidant, antiseptic, apirogen water etc.
The solid dosage forms of compound preparation of the present invention comprises capsule, tablet, pill, powder and granule.In these solid dosage formss, active component mixes with at least a conventional inert excipient (or carrier), as sodium citrate or dicalcium phosphate, or mixes with following compositions: (a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binding agent, for example, hydroxy methocel, alginate, gelatin, polyvinyl pyrrolidone, sucrose and arabic gum; (c) wetting agent, for example, glycerol; (d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example spermol and glyceryl monostearate; (h) adsorbent, for example, Kaolin; (i) lubricant, for example, Talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, dosage form also can comprise buffer agent.
Solid dosage forms such as tablet, sugar pill, capsule, pill and granule can adopt coating and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and, discharge in the mode that in this compound preparation, the release of active component can postpone certain part in digestive tract.The example of adoptable embedding component is polymeric material and Wax.In case of necessity, active component also can with above-mentioned excipient in one or more form microencapsulation form.
Preparation method
The below more specifically describes the preparation method of compound preparation of the present invention, but these concrete grammars do not consist of any restriction to the present invention.Compound preparation of the present invention can also be chosen various preparation methoies that will describe in this manual or known in the art wantonly and combines and make easily, and such combination can be easy to carry out by those skilled in the art in the invention.
The preparation method of concrete anti-AIDS compound preparation of the present invention comprises step:
A) with zidovudine, lamivudine, nevirapine and in add adjuvant and carry out pretreatment (as pulverizing or sieving), wherein, add adjuvant in described and comprise disintegrating agent and optional filler;
B) with pretreated zidovudine, lamivudine, nevirapine and in add adjuvant and mix (as put in wet granulator or blender and mix) after, obtain mixed material, and mixed material is carried out wet granulation (granulating or fluid-bed marumerization as adopting high shear to stir), thereby obtain the material through granulating;
C) material through granulating that step b is obtained and add adjuvant and mix after, carry out tabletting or capsule-filling and process, thereby obtain anti-AIDS compound tablet or capsule,
Wherein, the described adjuvant that adds comprises lubricant, optional disintegrating agent and optional filler;
In another preference, adding adjuvant in described is disintegrating agent and filler;
In another preference, the described adjuvant that adds is lubricant and disintegrating agent.
In another preference, the described adjuvant that adds is lubricant.
In another preference, the described adjuvant that adds is lubricant and filler.
In another preference, in described step b, wet granulation comprises: mixed material is mixed with binding agent, then granulate, wherein said binding agent is selected from lower group: starch slurry, polyvinylpyrrolidone, hypromellose, hyprolose or its combination.
In another preference, the wet granulation in described step b is to adopt high shear to stir to granulate or fluidized bed granulation.
In another preference, described step b also comprises: the material of granulating is carried out drying, thereby obtain drying, the material through granulating, wherein, described drying mode adopts carriage-type drying or fluid bed drying.
In another preference, described step b also comprises: the material through granulating is ground and granulate is processed, thereby obtain through grinding and the material of granulate.
A kind of preparation method of particularly preferred anti-AIDS compound preparation of the present invention comprises step:
1) with zidovudine, lamivudine, nevirapine and in add the adjuvant pretreatment of sieving;
2) take the pretreated zidovudine of 20-50wt%, the pretreated lamivudine of 10-30wt%, the pretreated nevirapine of 15-35wt% and 10-25wt% and add adjuvant in pretreated, after putting the middle mixing of wet granulator (or blender), add binding agent, then carry out wet granulation, thereby obtain the material through granulating;
3) with the material of step 2 gained in 40-80 ℃ of drying, thereby obtain the material of drying;
4) material with step 3 gained grinds and the granulate processing, thereby obtains the material through granulate;
5) add in the material of step 4 gained and add adjuvant, be placed in blender and mix, thereby obtain containing the material that adds adjuvant;
6) material with step 5 gained carries out tabletting and Cotton seeds, thereby obtains the anti-AIDS compound tablet;
Wherein above-mentioned percentage ratio is pressed the total restatement of compound preparation.
In another preference, described step 6) Cotton seeds in is processed for carry out film coating with high-efficiency coating machine.
Can use film coating pre-mix dose in described film coating processing procedure, described film coating pre-mix dose generally is comprised of plasticizer, film former, solid additive and auxiliary agent four parts, during production, these several materials are pre-mixed evenly according to certain formula, ratio and production technology, form a kind of complete production material, be commonly used to coating, commonly used have Opadry, prompt coloured silk, a Xin Feier etc.
In another preference, described step 6) process for step 5 gained material being carried out capsule charge, thus obtain the anti-AIDS compound capsule.
Described capsule-filling is treated to and uses capsule filling machine to carry out capsule-filling.
Major advantage of the present invention has:
(1) provide a kind of blend, each active component dissolution rate of anti-AIDS compound preparation that makes with described blend is high and stripping is abundant.
(2) anti-AIDS compound preparation of the present invention, described compound preparation dissolution rate is fast, and stripping is abundant.Stripping in 30 minutes can be greater than 85% in 0.1N hydrochloric acid, thereby active component is discharged rapidly, and this is very beneficial for the patient to the absorption of active component in described compound preparation.
(3) preparation method of anti-AIDS compound preparation of the present invention, technique is simply controlled, and good stability is easy to guarantee product quality.
Below in conjunction with concrete enforcement, further set forth the present invention.Should be understood that these embodiment only to be used for explanation the present invention and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise percentage ratio and umber calculate by weight.
Embodiment 1 tablet 1
Zidovudine, lamivudine, nevirapine, microcrystalline Cellulose (filler), carboxymethylstach sodium (disintegrating agent) are crossed 60 mesh sieve pretreatment, by mix homogeneously after the accurate weighing of recipe quantity (seeing Table 1), take the 2wt%HPMC aqueous solution as the binding agent wet granulation, 60 ℃ of dryings, granulate, add carboxymethylstach sodium (disintegrating agent), magnesium stearate (lubricant) to mix, even laggard interline health check-up is surveyed, tabletting carries out film coating with commercially available conventional high-efficiency coating machine BGB-150D (the little human relations in Zhejiang).
Table 1
| Composition | Unit dose | Percentage by weight |
| Zidovudine | 300mg | 36.4％ |
| Lamivudine | 150mg | 18.2％ |
| Nevirapine | 200mg | 24.2％ |
| Microcrystalline Cellulose (in add) | 100mg | 12.1％ |
| Carboxymethyl starch sodium (in add) | 22.5mg | 2.7％ |
| The 2wt%HPMC aqueous solution | In right amount | In right amount |
| Carboxymethyl starch sodium (adding) | 22.5mg | 2.7％ |
| Magnesium stearate (adding) | 5mg | 0.6％ |
| Film coating pre-mix dose | In right amount | 2.5％ |
| Gross weight | About 825mg | 100％ |
Embodiment 2 tablets 2
Zidovudine, lamivudine, nevirapine, microcrystalline Cellulose (filler), carboxymethylstach sodium (disintegrating agent) are crossed 40 mesh sieve pretreatment, by mix homogeneously after the accurate weighing of recipe quantity (seeing Table 2), take the 10wt%PVP aqueous solution as the binding agent wet granulation, 50 ℃ of dryings, granulate, add the laggard interline health check-up of magnesium stearate (lubricant) mix homogeneously to survey, tabletting carries out film coating with commercially available conventional high-efficiency coating machine BGB-150D (the little human relations in Zhejiang).
Table 2
| Composition | Unit dose | Percentage by weight |
| Zidovudine | 300mg | 36.4％ |
| Lamivudine | 150mg | 18.2％ |
| Nevirapine | 200mg | 24.2％ |
| Microcrystalline Cellulose (in add) | 85mg | 10.3％ |
| Carboxymethyl starch sodium (in add) | 60mg | 7.3％ |
| The 10wt%PVP aqueous solution | In right amount | In right amount |
| Magnesium stearate (adding) | 5mg | 0.6％ |
| Film coating pre-mix dose | In right amount | 2.5％ |
| Gross weight | About 825mg | 100％ |
Embodiment 3 tablets 3
Zidovudine, lamivudine, nevirapine, microcrystalline Cellulose (filler), modified starch (disintegrating agent) are crossed 40 mesh sieve pretreatment, by mix homogeneously after the accurate weighing of recipe quantity (seeing Table 3), take the 2wt%HPMC aqueous solution as the binding agent wet granulation, 80 ℃ of dryings, granulate, add modified starch (disintegrating agent), the laggard interline health check-up of magnesium stearate (lubricant) mix homogeneously to survey, tabletting carries out film coating with commercially available conventional high-efficiency coating machine BGB-150D (the little human relations in Zhejiang).
Table 3
| Composition | Unit dose | Percentage by weight |
| Zidovudine | 300mg | 36.4％ |
| Lamivudine | 150mg | 18.2％ |
| Nevirapine | 200mg | 24.2％ |
| Microcrystalline Cellulose (in add) | 95mg | 11.5％ |
| Modified starch (in add) | 25mg | 3.0％ |
| The 2wt%HPMC aqueous solution | In right amount | In right amount |
| Modified starch (adding) | 25mg | 3.0％ |
| Magnesium stearate (adding) | 5mg | 0.6％ |
| Film coating pre-mix dose | In right amount | 2.5％ |
| Gross weight | About 5mg | 100％ |
Embodiment 4 tablets 4
Zidovudine, lamivudine, nevirapine, microcrystalline Cellulose (filler), cross-linking sodium carboxymethyl cellulose (disintegrating agent) are crossed 60 mesh sieve pretreatment, by mix homogeneously after the accurate weighing of recipe quantity (seeing Table 4), take the 2wt%HPMC aqueous solution as the binding agent wet granulation, 65 ℃ of dryings, granulate, add pregelatinized Starch (filler), the laggard interline health check-up of magnesium stearate (lubricant) mix homogeneously to survey, tabletting carries out film coating with commercially available conventional high-efficiency coating machine BGB-150D (the little human relations in Zhejiang).
Table 4
| Composition | Unit dose | Percentage by weight |
| Zidovudine | 300mg | 36.4％ |
| Lamivudine | 150mg | 18.2％ |
| Nevirapine | 200mg | 24.2％ |
| Lactose (in add) | 80mg | 9.7％ |
| Cross-linking sodium carboxymethyl cellulose (in add) | 45mg | 5.5％ |
| The 2wt%HPMC aqueous solution | In right amount | In right amount |
| Pregelatinized Starch (adding) | 20mg | 2.4％ |
| Magnesium stearate (adding) | 5mg | 0.6％ |
| Film coating pre-mix dose | In right amount | 2.5％ |
| Gross weight | About 5mg | 100％ |
Embodiment 5 capsules 1
Zidovudine, lamivudine, nevirapine, microcrystalline Cellulose (filler), polyvinylpolypyrrolidone (disintegrating agent) are crossed 60 mesh sieve pretreatment, by mix homogeneously after the accurate weighing of recipe quantity (seeing Table 5), take the 5wt%HPC aqueous solution as the binding agent wet granulation, 40 ℃ of dryings, granulate, add the laggard interline health check-up of magnesium stearate (lubricant) mix homogeneously to survey, carry out capsule charge with commercially available fully-automatic capsule filling machine GKF2000 (German Bosch).
Table 5
| Composition | Unit dose | Percentage by weight |
| Zidovudine | 150mg | 37.5％ |
| Lamivudine | 75mg | 18.8％ |
| Nevirapine | 100mg | 25％ |
| Microcrystalline Cellulose (in add) | 45mg | 11.2％ |
| Polyvinylpolypyrrolidone (in add) | 25mg | 6.2％ |
| The 5wt%HPC aqueous solution | In right amount | In right amount |
| Magnesium stearate (adding) | 3mg | 0.8％ |
| Gross weight | About 400mg | 100％ |
Embodiment 6 capsules 2
Zidovudine, lamivudine, nevirapine, lactose (filler), pregelatinized Starch (filler), carboxymethylcellulose calcium (disintegrating agent) are crossed 60 mesh sieve pretreatment, by mix homogeneously after the accurate weighing of recipe quantity (seeing Table 6), take the 2wt%HPMC aqueous solution as the binding agent wet granulation, 70 ℃ of dryings, granulate, add the laggard interline health check-up of magnesium stearate (lubricant) mix homogeneously to survey, carry out capsule charge with commercially available fully-automatic capsule filling machine GKF2000 (German Bosch).
Table 6
| Composition | Unit dose | Percentage by weight |
| Zidovudine | 150mg | 37.5％ |
| Lamivudine | 75mg | 18.8％ |
| Nevirapine | 100mg | 25％ |
| Lactose (in add) | 30mg | 7.5％ |
| Pregelatinized Starch (in add) | 15mg | 3.8％ |
| Carboxymethylcellulose calcium (in add) | 25mg | 6.2％ |
| The 2wt%HPMC aqueous solution | In right amount | In right amount |
| Magnesium stearate (adding) | 3mg | 0.8％ |
| Gross weight | About 400mg | 100％ |
Embodiment 7 stripping data tests
Method of testing 1:
Analyze tablet (capsule) sample of above-mentioned preparation, adopt the prepared tablet samples of dissolution methods analyst of Chinese Pharmacopoeia regulation.Use Chinese Pharmacopoeia dissolution method of testing (2010 editions two appendix XC the second methods), take 0.1mol/L hydrochloric acid solution 900ml as dissolution medium, rotating speed is per minute 50 to turn, 37 ℃ are carried out the stripping curve test, be respectively sample time 5,10,15,30,45 minutes, detection method is high performance liquid chromatogram.
Test result:
The stripping data of embodiment 1 tablet 1 are as shown in table 7.
Table 7
| 5 minutes | 10 minutes | 15 minutes | 30 minutes | 45 minutes | |
| Zidovudine | 83.8％ | 93.6％ | 96.1％ | 97.6％ | 97.9％ |
| Lamivudine | 90.3％ | 96.0％ | 97.2％ | 97.9％ | 97.9％ |
| Nevirapine | 88.5％ | 94.7％ | 96.2％ | 96.9％ | 96.9％ |
The stripping data of embodiment 2 tablets 2 are as shown in table 8.
Table 8
| 5 minutes | 10 minutes | 15 minutes | 30 minutes | 45 minutes | |
| Zidovudine | 72.7％ | 92.3％ | 95.6％ | 96.3％ | 96.3％ |
| Lamivudine | 80.4％ | 94.7％ | 96.2％ | 96.4％ | 96.2％ |
| Nevirapine | 72.7％ | 90.7％ | 94.4％ | 96.5％ | 96.7％ |
The stripping data of embodiment 3 tablets 3 are as shown in table 9.
Table 9
| 5 minutes | 10 minutes | 15 minutes | 30 minutes | 45 minutes | |
| Zidovudine | 79.2％ | 91.2％ | 93.2％ | 94.8％ | 95.5％ |
| Lamivudine | 85.2％ | 93.5％ | 95.0％ | 96.2％ | 96.6％ |
| Nevirapine | 71.1％ | 88.6％ | 91.9％ | 94.1％ | 94.9％ |
The stripping data of embodiment 4 tablets 4 are as shown in table 10.
Table 10
| 5 minutes | 10 minutes | 15 minutes | 30 minutes | 45 minutes | |
| Zidovudine | 84.0％ | 93.7％ | 96.8％ | 98.7％ | 99.2％ |
| Lamivudine | 92.0％ | 99.0％ | 99.3％ | 99.5％ | 99.8％ |
| Nevirapine | 89.9％ | 96.8％ | 98.1％ | 99.0％ | 99.2％ |
The stripping data of embodiment 5 capsules 1 are as shown in table 11.
Table 11
| 5 minutes | 10 minutes | 15 minutes | 30 minutes | 45 minutes | |
| Zidovudine | 45.0％ | 83.7％ | 93.5％ | 95.7％ | 99.8％ |
| Lamivudine | 50.3％ | 85.2％ | 95.0％ | 98.8％ | 99.7％ |
| Nevirapine | 41.9％ | 78.3％ | 92.1％ | 97.5％ | 97.9％ |
The stripping data of embodiment 6 capsules 2 are as shown in table 12.
Table 12
| 5 minutes | 10 minutes | 15 minutes | 30 minutes | 45 minutes | |
| Zidovudine | 39.8％ | 79.9％ | 92.6％ | 97.5％ | 99.1％ |
| Lamivudine | 42.0％ | 81.3％ | 94.6％ | 98.9％ | 99.6％ |
| Nevirapine | 37.6％ | 75.8％ | 90.8％ | 95.0％ | 97.8％ |
Method of testing 2:
Method of testing is with the method for testing 1 of embodiment 7, take 0.05mol/L hydrochloric acid solution 900ml as dissolution medium.The stripping data of embodiment 1 tablet 1 and the stripping data of embodiment 5 capsules 1 are tested.
Method of testing 3:
Method of testing is with the method for testing 1 of embodiment 7, take 0.01mol/L hydrochloric acid solution 900ml as dissolution medium.The stripping data of embodiment 1 tablet 1 and the stripping data of embodiment 5 capsules 1 are tested.
Result shows: under the condition of method of testing 2 and method of testing 3, in tablet 1 and capsule 1, zidovudine, lamivudine and nevirapine all have been far longer than 85% at the dissolution of 15 minutes.
The comparative example
Repeat the described method of embodiment 2 in WO2006/114709, zidovudine and lamivudine are mixed rear wet granulation with filler (microcrystalline Cellulose).Wet granulation after nevirapine mixes with filler (microcrystalline Cellulose and lactose), binding agent (polyvidone).Then, two kinds of granules are mixed, add the disintegrating agent (carboxymethylstach sodium, consumption are the total restatement 2.91wt% of compound preparation), fluidizer (colloid silicon carbon dioxide), the lubricant (magnesium stearate) that add to mix rear tabletting.
With measuring its solubility curve in WO2006/114709.Result is as shown in table 13: all greater than 85%, and nevirapine was only 83% in the time of 30 minutes in the time of 30 minutes for zidovudine and lamivudine In Vitro Dissolution.
Table 13
| 5 minutes | 10 minutes | 15 minutes | 30 minutes | 45 minutes | |
| Zidovudine | 88％ | 92％ | 94％ | 96％ | 97％ |
| Lamivudine | 89％ | 92％ | 94％ | 96％ | 97％ |
| Nevirapine | 57％ | 68％ | 75％ | 83％ | 86％ |
Discuss:
1. the stripping in 30 minutes in 0.1N, 0.05N or 0.01N hydrochloric acid of the compound preparation (especially Tablet and Capsula) of the method for the invention preparation far above 85%, obviously is better than the result of extraction of the compound preparation that makes with existing preparation method.
2. the dissolution result of the capsule that makes of the tablet that makes of comparing embodiment 1-4 and embodiment 5-6 as can be known: the dissolution of the preparation that the method for the invention prepares in the time of 30 minutes is all very good, and dissolution is all greater than 85% in 15 minutes, therefore the stripping of medicine is no longer the rate-limiting step of drug absorption, and the absorption of medicine only is subjected to the impact of gastric emptying.
All quote in this application as a reference at all documents that the present invention mentions, just as each piece document is quoted separately as a reference.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (15)
1. an anti-AIDS compound preparation, is characterized in that, comprises:
1) zidovudine or its pharmaceutically acceptable derivates of safety and treatment effective dose;
2) lamivudine or its pharmaceutically acceptable derivates of safety and treatment effective dose;
3) nevirapine or its pharmaceutically acceptable derivates of safety and treatment effective dose;
4) disintegrating agent;
5) pharmaceutically acceptable carrier or the adjuvant except disintegrating agent;
Wherein, the content of described disintegrating agent is the 4-15wt% of compound preparation gross weight.
2. anti-AIDS compound preparation as claimed in claim 1, is characterized in that, described compound preparation has following dissolution characteristic: the dissolution of 30 minutes is greater than 85% in the 0.1N hydrochloric acid solution.
3. anti-AIDS compound preparation as claimed in claim 2, is characterized in that, described compound preparation has following dissolution characteristic: the dissolution of 30 minutes is greater than 90%, more preferably greater than 94% in the 0.1N hydrochloric acid solution.
4. anti-AIDS compound preparation as claimed in claim 1, is characterized in that, described disintegrating agent is selected from lower group: modified starch, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpolypyrrolidone or its combination.
5. anti-AIDS compound preparation as claimed in claim 1, is characterized in that, the content of described disintegrating agent is the 4.5-15wt% of compound preparation gross weight, preferably, is 5-10wt%.
6. anti-AIDS compound preparation as claimed in claim 1, is characterized in that, described compound preparation comprises: tablet, capsule, granule or pill.
7. anti-AIDS compound preparation as claimed in claim 1, is characterized in that, described adjuvant is selected from lower group: filler, binding agent, lubricant, coloring agent, correctives or its combination.
8. anti-AIDS compound preparation as claimed in claim 7, is characterized in that,
Described filler is selected from lower group: starch, lactose, mannitol, Icing Sugar, microcrystalline Cellulose, pregelatinized Starch or its combination; And/or
Described binding agent is selected from lower group: starch slurry, polyvinylpyrrolidone (PVP), hypromellose (HPMC), hyprolose (HPC) or its combination; And/or
Described lubricant is selected from lower group: magnesium stearate, Pulvis Talci, micropowder silica gel or its combination.
9. anti-AIDS compound preparation as claimed in claim 1, it is characterized in that, for the compound preparation gross weight, the content of described zidovudine is 20-50wt%, the content of described lamivudine is 10-30wt%, and the content of described nevirapine is 15-35wt%.
10. anti-AIDS compound preparation as claimed in claim 1, is characterized in that, in described compound preparation, the per unit dosage form comprises 100～450mg zidovudine, 50～200mg lamivudine and 50～300mg nevirapine.
11. the preparation method of an anti-AIDS compound preparation is characterized in that, comprises step:
A) with zidovudine, lamivudine, nevirapine and in add adjuvant and carry out pretreatment, wherein, add adjuvant in described and comprise disintegrating agent and optional filler;
B) with pretreated zidovudine, lamivudine, nevirapine and in add adjuvant and mix after, obtain mixed material, and mixed material carried out wet granulation, thereby obtain material through granulating;
C) material through granulating that step b is obtained and add adjuvant and mix after, carry out tabletting or capsule-filling and process, thereby obtain anti-AIDS compound tablet or capsule;
Wherein, the described adjuvant that adds comprises lubricant, optional disintegrating agent and optional filler.
12. a blend is characterized in that, described blend is made of following component:
The first active component: zidovudine or its pharmaceutically acceptable derivates;
The second active component: lamivudine or its pharmaceutically acceptable derivates;
The 3rd active component: nevirapine or its pharmaceutically acceptable derivates; With
Disintegrating agent and optional filler;
And described blend is to form by described the first active component, the second active component, the 3rd active component and disintegrating agent and optional filler are mixed together.
13. blend as claimed in claim 12 is characterized in that, the weight ratio of the first active component, the second active component, the 3rd active component and disintegrating agent and optional filler is 20-50: 10-30: 15-35: 10-25.
14. a compound preparation is characterized in that, described compound preparation contains the described blend of claim 12 and pharmaceutically acceptable carrier.
15. compound preparation as claimed in claim 14 is characterized in that, the disintegrating agent in the disintegrating agent in described blend and described pharmaceutically acceptable carrier is the disintegrating agent of identical type.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103405440A (en) * | 2013-07-03 | 2013-11-27 | 上海美优制药有限公司 | Compound anti-AIDS (Acquired Immune Deficiency Syndrome) medicine orally taken suspension preparation |
| CN104784133A (en) * | 2014-01-19 | 2015-07-22 | 广东东阳光药业有限公司 | Zidovudine tablets and preparation method thereof |
| CN107334743A (en) * | 2016-07-15 | 2017-11-10 | 安徽贝克生物制药有限公司 | A kind of Zidovudine, Lamivudine, NVP Compound Tablet and preparation method thereof |
-
2011
- 2011-12-26 CN CN 201110442503 patent/CN103169728A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103405440A (en) * | 2013-07-03 | 2013-11-27 | 上海美优制药有限公司 | Compound anti-AIDS (Acquired Immune Deficiency Syndrome) medicine orally taken suspension preparation |
| CN104784133A (en) * | 2014-01-19 | 2015-07-22 | 广东东阳光药业有限公司 | Zidovudine tablets and preparation method thereof |
| CN107334743A (en) * | 2016-07-15 | 2017-11-10 | 安徽贝克生物制药有限公司 | A kind of Zidovudine, Lamivudine, NVP Compound Tablet and preparation method thereof |
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Application publication date: 20130626 |