CN1792363A - Medicinal composition contg. IDV and valproic acid or salts thereof - Google Patents
Medicinal composition contg. IDV and valproic acid or salts thereof Download PDFInfo
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- CN1792363A CN1792363A CN 200510086717 CN200510086717A CN1792363A CN 1792363 A CN1792363 A CN 1792363A CN 200510086717 CN200510086717 CN 200510086717 CN 200510086717 A CN200510086717 A CN 200510086717A CN 1792363 A CN1792363 A CN 1792363A
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Abstract
A composite medicine for treating AIDS and ARC and killing HIV is prepared from the Yindinawei (0.1-95 Wt%), propylphocenic acid or its salt (10.-95), and medicinal auxiliary (4-98.9).
Description
Technical field
The present invention relates to a kind of Pharmaceutical composition that contains indinavir and valproic acid or its salt that is used for the treatment of the acquired immunodeficiency syndrome that HIV (human immunodeficiency virus) infection causes.
Background technology
HIV (human immunodeficiency virus) (human immunodeficiency virus, HIV) infect acquired immunodeficiency syndrome (the aquired immunodeficiency syndrome that causes, AIDS) be commonly called as acquired immune deficiency syndrome (AIDS), just worldwide be widely current at present, become great public health and social problem highly visible.It is generally acknowledged that now HIV is the relevant syndrome with AIDS of AIDS (AIDS-related complex, pathogenic factor ARC).Not only HIV is the main cause of AIDS, and the HIV infection can be passed in time usually and be caused immunodeficiency extremely separately, and patient is caused death.Because the public's attention, HIV also becomes and studies one of deep virus in history.Although scientist has done effort, still this fatal disease can't effectively even there be satisfied Therapeutic Method.
Domestic HIV (human immunodeficiency virus) infection number rises year by year, and at present number every year of China's aids infection, as not taking active and effective control, by 2010, China's patients infected hiv will be above 1,000 ten thousand people with 30% speed increase.At present, the medicine of world's listing treatment HIV virus has twenties kinds, domestic imitation patent expired and not at 5 kinds of essential drugses of the row of administrative protection, filled up the blank of state's internal therapy AIDS-treating medicine.But the simple and not high therapeutic effect that greatly reduces medicine of drug quality of listing dosage form.
(highly-active antiretroviral therapy HAART), is acknowledged as a milestone on the treating AIDS to " highly active antiretroviral therapy " that scientist Chinese descendant in America He Dayi proposes.The therapeutic modality of this drug combination generically is called " HAART " again, it is by suppressing virus replication, recovering immune function of human body, improved the therapeutic effect of acquired immune deficiency syndrome (AIDS) significantly, reduced mortality rate, thereby develop into the conventional treatments of acquired immune deficiency syndrome (AIDS) gradually, and worldwide (especially in American-European countries) is widely used.However, nearly 10 years clinical practice shows, HAART and unlike what people expected can thoroughly be removed HIV (human immunodeficiency virus) in the infected's body, " cocktail " of this both expensive be thorough treatment of AIDS also at present, and needs of patients is accepted lifelong treatment.An important reasons that causes this situation is exactly to be in " resting state " after some virus is entering the immunocyte of human body.Thisly stop to duplicate, do not have active virus " to hide " in cell, antiviral drugs just can't be killed them, in case and patient stops using antiviral drugs, these viruses can " be revived " again again, enter replication status, cause new infection, " HAART " also has some shortcomings of can not ignore except costing an arm and a leg.The one, side effect, digestive tract reaction often appears in this therapy, as nausea,vomiting,diarrhea etc.; Also suppress the bone marrow hematogenesis function, cause serious anemia; In addition, also can cause lipodystrophy, as buffalo hump, spider-man and central obesity etc.; The 2nd, drug resistance, medication is after 3,4 months, and effect is just bad, must select medicine again.
" lancet " on August 13rd, 2005
[1]In the research report of magazine, David's mug(unit of measure) doctor Li Si of North Carolina, US university leader's research group is used for a kind of antuepileptic-valproic acid (valproic acid) commonly used the treatment of acquired immune deficiency syndrome (AIDS).This method can be removed the HIV (human immunodeficiency virus) that hides in human body cell, escapes the medicine attack.Valproic acid or its salt have the effect of synthesizing and block its degraded that promotion reaches central nervous system's inhibitory transmitter γ-An Jidingsuan on every side; can inhibition of histone acetylase I; thereby stop HIV to hide for a long time in the CD4+ of human body cell with state static, that hide; the effect of valproic acid is the virus of " waking up " resting state, and just can be killed by effective antiviral drugs behind the activated viral.The advantage of valproic acid or its salt is that it is a kind of by clear cognitive medicine, is used to the long-term treatment of epilepsy, migraine and emotional maladjustment.Most of people have good toleration to it, and total fatality rate is 1: 51, and 300 (Bryant AE, the neurological 1986,40:465-469).
Hiv protease is that the viral polymeric protein precursor of finding in traditional HIV that makes is cracked into the proteic a kind of enzyme of individual feature.Indinavir (Indinavir) is the protease inhibitor that a kind of HIV of being used for the treatment of infects, and can combine and suppress its activity with this protease activities position.This inhibitory action has been blocked the cracking of viral polymeric protein, causes jejune non-infectious virion to form.The purposes of indinavir and anti-HIV thereof is described in EP0382526 and WO91/17159, can be used for treating adult's HIV infection.The medical insurance catalogue that has at present entered China is one of essential drugs of treatment acquired immune deficiency syndrome (AIDS).
Summary of the invention
An object of the present invention is to provide and a kind ofly can activate the effective Pharmaceutical composition that hides the HIV that in cell, is in resting state, in the hope of removing the HIV virus that is in state of activation and resting state in the body simultaneously.
Another object of the present invention is to provide a kind of new Pharmaceutical composition that obtains being characterized as pharmaceutically acceptable homogeneous mixture that active constituent is mixed for treatment AIDS.
The 3rd purpose of the present invention is to reduce the untoward reaction that three or tetrad medication commonly used are at present brought, and reduces the expense of treatment AIDS, so that the therapeutic scheme of AIDS can be popularized in China and other developing countries.
The present invention relates to comprise the therapeutics combination of indinavir and valproic acid or its salt, the formula range of its Pharmaceutical composition (all calculating by weight percentage): indinavir is 0.1～95%, and valproic acid or its salt are 1.0%～95%, pharmaceutic adjuvant 4～98.9%.Be used for the treatment of HIV (human immunodeficiency virus) (HIV) and infect, and be used in particular for treating AIDS or the relevant syndrome of AIDS (ARC).In the per unit dosage form, preferably contain the indinavir of 100～400mg and valproic acid or its salt of 75～300mg, and the acceptable accessories that accounts for unit dosage forms gross weight 20%～35%.
Indinavir, chemistry (2R, suitable)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolane-5-yl) by name-pyrimid-2-one, English name Indinavir is in European patent specification No.0,382, elaborate in 526, be a kind of hiv protease inhibitor, its structural formula is as follows:
Valproic acid, chemistry 2-Propylpentanoic by name is a kind of acetylation of histone enzyme inhibitor, its structural formula is as follows:
Term " evenly " refers in this article that these active constituents are dispersed in basically and contains their whole and make in the tablet that the uniformity of active constituent can detect by the medicine uniformity and determine in tablet.
Term " safety and effective dose " refers to the performance preparation function sought by research worker or clinician in this article and the patient's of this preparation the amount of preparation of tissue is accepted in not serious infringement.
Related indinavir also comprises its pharmaceutically acceptable indinavir sulfate among the present invention.
Valproic acid and salt thereof related among the present invention comprise pharmaceutically acceptable valproic acid, sodium valproate, magnesium valproate and valproic acid calcium etc., comprise that also valproic acid is at the pharmaceutically acceptable derivates valpromide.
The preparation supplementary material:
The lubricant of disintegrating agent, safety and the effective dose of binding agent, safety and the effective dose of diluent, safety and the effective dose of the optionally safe in utilization and effective dose of Pharmaceutical composition of the present invention and other pharmaceutically acceptable coloring agent and correctivess of safety and effective dose.
The Pharmaceutical composition that contains indinavir and valproic acid or its salt is based on 100% of gross weight, contain: 1. 0.1～95% indinavir, 2. 1.0～95% valproic acid or its salt, 3. 0～35% diluent, 4. 0～20% binding agent, 5. 6. 0～10% lubricant and 7. other pharmaceutically acceptable coloring agent and/or correctivess of 0～10% of 0～30% disintegrating agent.
Diluent used among the present invention is in order to increase the weight and volume of preparation, can be that one or more can provide the volumes of formulation of acquisition expectation or the chemical compound of weight, comprise in lactose, sucrose, mannitol, sorbitol, starch, pregelatinized Starch, cellulose, processing agar, glucose, dicalcium phosphate, calcium hydrogen phosphate, gelatin or the dextrin one or more.
Binding agent among the present invention is to be used for granulating and the adherent adjuvant of tabletting, comprises the water of one or more adjuvants in water, ethanol, tween 80, polyvinylpyrrolidone (PVP), methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium alginate, aluminium-magnesium silicate, arabic gum or the Polyethylene Glycol or the solution of alcohol.
Disintegrating agent among the present invention is disintegrate when being used to promote the preparation of preparation of compositions to contact with aqueous medium, comprises in carboxymethyl starch sodium (CMS-Na), crosslinked carboxymethyl fecula sodium (cCMS-Na), low-substituted hydroxypropyl cellulose (LHPC), crospolyvinylpyrrolidone (PVPP), AmberliteIRP-88, sodium carboxymethyl cellulose (CMC-Na), cross-linking sodium carboxymethyl cellulose (cCMC-Na), carboxymethylcellulose calcium or the microcrystalline Cellulose (MCC) one or more.
Lubricant among the present invention is in order to feed in raw material smoothly and slice, comprises in magnesium stearate, calcium stearate, stearic acid, Polyethylene Glycol, silicon dioxide, micropowder silica gel, Pulvis Talci, aluminium hydroxide, alginic acid, natural gum or the Stepanol MG one or more
Pharmaceutically acceptable coloring agent of among the present invention other and correctives comprise red, red scarlet, the light blue of coloring agent lemon yellow, sunset yellow, carmine, amaranth, temptation, indigo, light green, egg yolk and medicinal color lake and correctives A Siba is sweet, in glycyrrhizin, stevioside, saccharin sodium or the medicinal essence one or more.
The present invention preferably exists with the form of the pharmaceutical preparation that is suitable for oral administration.These preparations can exist with discontinuous unit easily, as tablet, scrotiform tablet, capsule or be suitable for any other oral and compatible with present composition preparation, wherein contain the active constituent of each scheduled volume.Shi Yi preparation can be by direct compacting or method of granulating preparation especially, and these preparations can contain conventional excipients such as binding agent, disintegrating agent, antitack agent and the lubricant etc. of safety and effective dose.Tablet also can carry out coating according to any method well known by persons skilled in the art, and this coating does not hinder the releasing properties of tablet, or other physics of the present invention or chemical property.Above-mentioned preparation can also be modified by any method known to those skilled in the art to obtain the slow release of active constituent, and these preparations can also contain other active constituents of safety and effective dose, as antibacterial or antiseptic.
Pharmaceutical composition of the present invention can be used as the ingredient and the other drug preparation of therapeutic scheme and unites use.
Pharmaceutical composition of the present invention can also be packaged as goods, and these goods contain the indinavir of safety and treatment effective dose, and valproic acid or its salt or the valpromide of safety and treatment effective dose.
Any packing well known by persons skilled in the art is suitable for oral tablet, scrotiform tablet or other solid dosage formss and can not destroys the distinct methods of component of the present invention, is applicable to and packs.The tablet, scrotiform tablet or other solid dosage formss that are suitable for oral administration can be packed and are contained in the multiple packaging material, particularly glass and plastic bottle also can be packaged in the unit dose blister packs.Can also print relevant label and the information of Pharmaceutical composition therewith on these packaging material.In addition, goods can comprise pamphlet, report or the leaflet that contains product information.This of pharmaceutical dosage form kind of form is called " adnexa in the packing " in pharmaceuticals industry.Adnexa can be attached to or be included in the pharmacy goods in the packing.Adnexa and any goods label provide the information relevant with Pharmaceutical composition in the packing.
Pharmaceutical composition of the present invention can be with being fit to normally used method of technical staff and technology preparation its physics and chemical characteristic and prepare peroral dosage form by direct compacting or method of granulating.
The invention effect:
David's mug(unit of measure) doctor Li Si in North Carolina, US university
[1]Research group valproic acid (valproic acid) is used for the test of the treatment of acquired immune deficiency syndrome (AIDS), screened the contraindication that does not have the valproic acid treatment, the AIDS the infected who does not accept interferon and the treatment of other immunomodulators, had 4 AIDS the infecteds and accepted this new therapeutic scheme.These the infecteds are after accepting HAART; Accepted again 3 months oral valproic acid (500-750mg/ days, bid) treatment.In the front and back that giving valproic acid treatment, cultivate the CD4+ cell of dormancy by limiting dilution assay, and the CD4+T cell of dormancy with latent infection is carried out quantitative assay.Result of the test shows, before adding valproic acid, the frequency that rest cell infects is stable, but after giving, just begin to reduce, this minimizing all is tangible in four patients' three people, in accepting the AIDSinfected patient of this therapeutic trial, there is HIV (human immunodeficiency virus) hiding in 3 human bodies obviously to reduce, amount of decrease reaches 75%.
Above-mentioned evidence is removed the CD4+T cell that can increase HIV dormancy in body safely as valproic acid or its salt of acetylation of histone enzyme inhibitor.Indinavir is as the inhibitor of hiv protease, can combine with the active site of this enzyme and suppresses its activity, and this inhibitory action has been blocked the cracking of viral polymeric protein, causes jejune non-infectious virion to form, thereby kills the HIV that is activated.Therefore, above-mentioned Pharmaceutical composition not only can be removed the HIV that is activated, and can also remove the HIV that hides in human body cell, escapes the medicine attack.
Pharmaceutical composition of the present invention can be used as effective Drug therapy HIV-I and infects, and AIDS provides a kind of new way for treatment.
The specific embodiment
The following example has further described and has illustrated the particular in the scope of the invention.The embodiment that provides just illustrates, and is not will be as restriction, because under the prerequisite that does not deviate from the spirit and scope of the present invention, a lot of versions are possible.
Embodiment 1
1. the direct compacting preparation of the tablet of sulfur acid indinavir and valproic acid.
| Component | Content (g)/1000 slice |
| Indinavir sulfate | 400 |
| Valproic acid | 150 |
| 95% ethanol | 7.5 |
| Microcrystalline Cellulose | 95 |
| CMC-Na | 20 |
| Magnesium stearate | 7.5 |
| Lactose | The surplus of gross weight |
| Gross weight | 750 |
2. preparation method:
Indinavir sulfate, valproic acid, lactose, microcrystalline Cellulose and the CMC-Na of above-mentioned recipe quantity are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% alcoholic solution and make soft material in right amount, 18 mesh sieves are granulated, in 80 ℃ of dryings, 18 mesh sieve granulate add magnesium stearate and make mixing behind the lubricant, tabletting, every heavy 0.75g.
Embodiment 2
1. the direct compacting preparation of the tablet of sulfur acid indinavir and sodium valproate.
| Component | Content (g)/1000 slice |
| Indinavir sulfate | 400 |
| Sodium valproate | 200 |
| Pregelatinized Starch | 60 |
| 95% ethanol | 7 |
| 2% tween | 12 |
| CMS-Na | 20 |
| Magnesium stearate | 8 |
| Microcrystalline Cellulose | The surplus of gross weight |
| Gross weight | 800 |
2. preparation method
Indinavir sulfate, sodium valproate, pregelatinized Starch, microcrystalline Cellulose and the CMS-Na of above-mentioned recipe quantity are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% ethanol and 2% tween solution and make soft material in right amount, 18 mesh sieves are granulated, in 50-60 ℃ of drying, 18 mesh sieve granulate add magnesium stearate and make mixing behind the lubricant, tabletting, every heavy 0.80g.
Embodiment 3
1. the direct compacting preparation that contains the tablet of indinavir and sodium valproate.
| Component | Content (g)/1000 slice |
| Indinavir | 300 |
| Sodium valproate | 100 |
| Pregelatinized Starch | 50 |
| 95% ethanol | 5.5 |
| 1％PVP | 6 |
| CMS-Na | 11 |
| Magnesium stearate | 6 |
| Lactose | The surplus of gross weight |
| Gross weight | 550 |
2. preparation method
Indinavir, sodium valproate, pregelatinized Starch, lactose, the CMS-Na of above-mentioned recipe quantity are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% ethanol and 1%PVP solution and make soft material in right amount, 18 mesh sieves are granulated, in 50-60 ℃ of drying, 18 mesh sieve granulate add magnesium stearate and make mixing behind the lubricant, tabletting, every heavy 0.55g.
Embodiment 4
1. the direct compacting preparation of the tablet of sulfur acid indinavir and valproic acid.
| Component | Content (g)/1000 slice |
| Indinavir sulfate | 300 |
| Valproic acid | 75 |
| cCMS-Na | 25 |
| 95% ethanol | 5 |
| Stearic acid | 2.5 |
| Lactose | The surplus of gross weight |
| Gross weight | 500 |
2. preparation method
Indinavir sulfate, valproic acid, lactose, the cCMS-Na of above-mentioned recipe quantity are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% ethanol and make soft material in right amount, 18 mesh sieves are granulated, in 80 ℃ of dryings, 18 mesh sieve granulate add hard ester acid and make mixing behind the lubricant, tabletting, every heavy 0.50g.
Embodiment 5
1. the direct compacting preparation of the tablet of sulfur acid indinavir and magnesium valproate.
| Component | Content (g)/1000 slice |
| Indinavir sulfate | 350 |
| Magnesium valproate | 275 |
| 95% ethanol | 8.5 |
| Microcrystalline Cellulose | 85 |
| CMC | 26 |
| Magnesium stearate | 9.5 |
| Lactose | The surplus of gross weight |
| Gross weight | 850 |
2. preparation method:
Indinavir sulfate, valproic acid, lactose, microcrystalline Cellulose and the CMC-Na of above-mentioned recipe quantity are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% alcoholic solution and make soft material in right amount, 18 mesh sieves are granulated, in 80 ℃ of dryings, 18 mesh sieve granulate add magnesium stearate and make mixing behind the lubricant, tabletting, every heavy 0.85g.
Embodiment 6
1. the direct compacting preparation of the tablet of sulfur acid indinavir and magnesium valproate.
| Component | Content (g)/1000 slice |
| Indinavir sulfate | 150 |
| Magnesium valproate | 125 |
| Starch | 90 |
| 95% ethanol | 4.2 |
| CMC-Na | 26 |
| Magnesium stearate | 9.5 |
| Microcrystalline Cellulose | The surplus of gross weight |
| Gross weight | 420 |
2. preparation method:
Indinavir sulfate, valproic acid, lactose, microcrystalline Cellulose and the CMC-Na of above-mentioned recipe quantity are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% alcoholic solution and make soft material in right amount, 18 mesh sieves are granulated, in 80 ℃ of dryings, 18 mesh sieve granulate add magnesium stearate and make mixing behind the lubricant, tabletting, every heavy 0.42g.
Embodiment 7
1. the direct compacting preparation of the tablet of sulfur acid indinavir and valproic acid calcium.
| Component | Content (g)/1000 slice |
| Indinavir sulfate | 350 |
| Valproic acid calcium | 200 |
| Pregelatinized Starch | 60 |
| 95% ethanol | 7.5 |
| 2% tween | 12 |
| cCMS | 15 |
| Calcium stearate | 4.5 |
| Microcrystalline Cellulose | The surplus of gross weight |
| Gross weight | 750 |
2. preparation method
Indinavir sulfate, sodium valproate, pregelatinized Starch, microcrystalline Cellulose and the CMS-Na of above-mentioned recipe quantity are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% ethanol and 2% tween solution and make soft material in right amount, 18 mesh sieves are granulated, in 50-60 ℃ of drying, 18 mesh sieve granulate add calcium stearate and make mixing behind the lubricant, tabletting, every heavy 0.75g.
Embodiment 8
1. the direct compacting preparation of the tablet of sulfur acid indinavir and valpromide.
| Component | Content (g)/1000 slice |
| Indinavir sulfate | 350 |
| Valpromide | 100 |
| Microcrystalline Cellulose | 90 |
| 95% ethanol | 7.5 |
| 2% tween | 6 |
| CMS-Na | 12 |
| Magnesium stearate | 6 |
| Pregelatinized Starch | The surplus of gross weight |
| Gross weight | 600 |
2. preparation method
Indinavir sulfate, sodium valproate, pregelatinized Starch, microcrystalline Cellulose and the CMS-Na of above-mentioned recipe quantity are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% ethanol and 2% tween solution and make soft material in right amount, 18 mesh sieves are granulated, in 50-60 ℃ of drying, 18 mesh sieve granulate add magnesium stearate and make mixing behind the lubricant, tabletting, every heavy 0.60g.
The Performance Detection of each sample strip of gained among the embodiment 1-8;
| Embodiment | Outward appearance | Hardness/kg | Dissolution/% |
| 1 | Bright and clean | 4.2±0.2 | 85 |
| 2 | Bright and clean | 4.0±0.4 | 93 |
| 3 | Bright and clean | 4.8±0.1 | 87 |
| 4 | Bright and clean | 4.0±0.3 | 82 |
| 5 | Bright and clean | 4.5±0.5 | 88 |
| 6 | Bright and clean | 4.5±0.2 | 86 |
| 7 | Bright and clean | 4.6±0.4 | 85 |
| 8 | Bright and clean | 4.0±0.3 | 82 |
Embodiment 9
1. the direct compacting preparation of the tablet of sulfur acid indinavir and valproic acid.
| Component | Content (g)/1000 slice |
| Indinavir sulfate | 350 |
| Valproic acid | 250 |
| 95% ethanol | 8.5 |
| Microcrystalline Cellulose | 85 |
| CMC | 26 |
| Magnesium stearate | 9.5 |
| Indigo | 0.39 |
| Lactose | The surplus of gross weight |
| Gross weight | 780 |
2. preparation method:
Indinavir sulfate, valproic acid, lactose, microcrystalline Cellulose and the CMC-Na of above-mentioned recipe quantity are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% alcoholic solution and make soft material in right amount, 18 mesh sieves are granulated, in 80 ℃ of dryings, 18 mesh sieve granulate add magnesium stearate and make mixing behind the lubricant, tabletting, every heavy 0.78g.
Embodiment 10
1. the direct compacting preparation of the tablet of sulfur acid indinavir and sodium valproate.
| Component | Content (g)/1000 slice |
| Indinavir sulfate | 175 |
| Sodium valproate | 150 |
| Starch | 45 |
| 95% ethanol | 4.2 |
| CMC-Na | 26 |
| Stearic acid | 9.5 |
| Light green | 0.22 |
| Microcrystalline Cellulose | The surplus of gross weight |
| Gross weight | 450 |
2. preparation method:
The indinavir sulfate of above-mentioned recipe quantity, valproic acid, lactose, microcrystalline Cellulose, light green and CMC-Na are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% alcoholic solution and make soft material in right amount, 18 mesh sieves are granulated, in 80 ℃ of dryings, 18 mesh sieve granulate add hard ester acid and make mixing behind the lubricant, tabletting, every heavy 0.45g.
Embodiment 11
1. the direct compacting preparation that contains the tablet of indinavir and valproic acid calcium.
| Component | Content (g)/1000 slice |
| Indinavir | 350 |
| Valproic acid calcium | 225 |
| Pregelatinized Starch | 75 |
| 95% ethanol | 7.5 |
| 2% tween | 12 |
| cCMS | 15 |
| Calcium stearate | 4.5 |
| Sunset yellow | 0.35 |
| Cellulose | The surplus of gross weight |
| Gross weight | 750 |
2. preparation method
Indinavir, valproic acid calcium, pregelatinized Starch, cCMS, cellulose and the sunset yellow of above-mentioned recipe quantity are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% ethanol and 2% tween solution and make soft material in right amount, 18 mesh sieves are granulated, in 50-60 ℃ of drying, 18 mesh sieve granulate add calcium stearate and make mixing behind the lubricant, tabletting, every heavy 0.75g.
Embodiment 12
1. the direct compacting preparation of the tablet of sulfur acid indinavir and valpromide.
| Component | Content (g)/1000 slice |
| Indinavir sulfate | 325 |
| Valpromide | 100 |
| Microcrystalline Cellulose | 90 |
| 95% ethanol | 7.5 |
| 2% tween | 6 |
| CMS-Na | 12 |
| Micropowder silica gel | 6 |
| Lemon yellow | 0.25 |
| Starch | The surplus of gross weight |
| Gross weight | 550 |
2. preparation method
Indinavir sulfate, valpromide, starch, microcrystalline Cellulose, CMS-Na and the lemon yellow of above-mentioned recipe quantity are crossed 80 mesh sieves, mix homogeneously, cross 40 mesh sieves, add binding agent 95% ethanol and 2% tween solution and make soft material in right amount, 18 mesh sieves are granulated, in 50-60 ℃ of drying, 18 mesh sieve granulate add magnesium stearate and make mixing behind the lubricant, tabletting, every heavy 0.55g.
Embodiment 13
1. the capsule of sulfur acid indinavir and valproic acid.
| Component | Content (g)/1000 |
| Indinavir | 300 |
| Valproic acid | 75 |
| Lactose | 80 |
| cCMS-Na | 25 |
| Magnesium stearate | 10 |
| Gross weight | 490 |
2. preparation method
After above-mentioned recipe quantity raw material pulverizing crossed 60 mesh sieves, mix homogeneously was crossed 40 mesh sieves, adds magnesium stearate, and fill 1 behind the mix homogeneously
#Capsule, the tolerant heavy about 0.49g of every intragranular.
Embodiment 14
1. the capsule of sulfur acid indinavir and sodium valproate.
| Component | Content (g)/1000 |
| Indinavir | 300 |
| Sodium valproate | 100 |
| Microcrystalline Cellulose | 50 |
| CMS-Na | 35 |
| Magnesium stearate | 15 |
| Gross weight | 500 |
2. preparation method
After above-mentioned recipe quantity raw material pulverizing crossed 60 mesh sieves, mix homogeneously was crossed 40 mesh sieves, adds magnesium stearate, and fill 1 behind the mix homogeneously
#Capsule, the tolerant heavy about 0.50g of every intragranular.
Embodiment 15
1. the capsule of sulfur acid indinavir and valproic acid.
| Component | Content (g)/1000 |
| Indinavir sulfate | 300 |
| Valproic acid | 75 |
| Lactose | 80 |
| cCMS-Na | 25 |
| Stearic acid | 10 |
| Gross weight | 490 |
2. preparation method
After above-mentioned recipe quantity raw material pulverizing crossed 60 mesh sieves, mix homogeneously was crossed 40 mesh sieves, adds stearic acid, and fill 1 behind the mix homogeneously
#Capsule, the tolerant heavy about 0.49g of every intragranular.
Embodiment 16
1. the capsule of sulfur acid indinavir and sodium valproate
| Component | Content (g)/1000 |
| Indinavir sulfate | 300 |
| Sodium valproate | 100 |
| Microcrystalline Cellulose | 50 |
| CMS-Na | 35 |
| Magnesium stearate | 15 |
| Gross weight | 500 |
2. preparation method
After above-mentioned recipe quantity raw material pulverizing crossed 60 mesh sieves, mix homogeneously was crossed 40 mesh sieves, adds magnesium stearate, and fill 1 behind the mix homogeneously
#Capsule, the tolerant heavy about 0.50g of every intragranular.
Embodiment 17
1. the capsule that contains indinavir and magnesium valproate
| Component | Content (g)/1000 |
| Indinavir | 300 |
| Magnesium valproate | 175 |
| Lactose | 90 |
| cCMS-Na | 25 |
| Magnesium stearate | 10 |
| Gross weight | 600 |
2. preparation method
After above-mentioned recipe quantity raw material pulverizing crossed 60 mesh sieves, mix homogeneously was crossed 40 mesh sieves, adds magnesium stearate, and fill 0 behind the mix homogeneously
#Capsule, the tolerant heavy about 0.60g of every intragranular.
Embodiment 18
1. the capsule that contains indinavir and valproic acid calcium
| Component | Content (g)/1000 |
| Indinavir | 300 |
| Valproic acid calcium | 100 |
| Microcrystalline Cellulose | 50 |
| CMS-Na | 35 |
| Calcium stearate | 15 |
| Gross weight | 500 |
2. preparation method
After above-mentioned recipe quantity raw material pulverizing crossed 60 mesh sieves, mix homogeneously was crossed 40 mesh sieves, adds calcium stearate, and fill 1 behind the mix homogeneously
#Capsule, the tolerant heavy about 0.50g of every intragranular.
Embodiment 19
1. the capsule that contains indinavir and valpromide
| Component | Content (g)/1000 |
| Indinavir | 300 |
| Valpromide | 75 |
| Lactose | 80 |
| cCMS-Na | 25 |
| Stearic acid | 10 |
| Gross weight | 490 |
2. preparation method
After above-mentioned recipe quantity raw material pulverizing crossed 60 mesh sieves, mix homogeneously was crossed 40 mesh sieves, adds stearic acid, and fill 1 behind the mix homogeneously
#Capsule, the tolerant heavy about 0.49g of every intragranular.
Embodiment 20
1. the capsule of sulfur acid indinavir and valpromide.
| Component | Content (g)/1000 |
| Indinavir sulfate | 350 |
| Valpromide | 100 |
| Microcrystalline Cellulose | 50 |
| CMS-Na | 35 |
| Stearic acid | 15 |
| Gross weight | 550 |
2. preparation method
After above-mentioned recipe quantity raw material pulverizing crossed 60 mesh sieves, mix homogeneously was crossed 40 mesh sieves, adds stearic acid, and fill 1 behind the mix homogeneously
#Capsule, the tolerant heavy about 0.55g of every intragranular.
Claims (10)
1. Pharmaceutical composition that contains indinavir and valproic acid or its salt, it is characterized in that: it contains indinavir, chemistry (2R by name, suitable)-4-amino-1-(2-hydroxymethyl-1, the 3-oxathiolane-5-yl)-pyrimid-2-one and valproic acid or its salt, the formula range of its Pharmaceutical composition is calculated by weight percentage: indinavir is 0.1～95%, valproic acid or its salt are 1.0%～95%, pharmaceutic adjuvant 4～98.9%, pharmaceutic adjuvant are diluent, binding agent, disintegrating agent, lubricant, coloring agent and/or correctives.
2. the Pharmaceutical composition that contains indinavir and valproic acid or its salt according to claim 1, it is characterized in that: in the per unit dosage form, contain 100～400mg indinavir, 50～500mg valproic acid or its salt and account for the pharmaceutic adjuvant of unit dosage forms gross weight 20%～35%, pharmaceutic adjuvant is diluent, binding agent, disintegrating agent, lubricant, coloring agent and/or correctives.
3. the Pharmaceutical composition that contains indinavir and valproic acid or its salt according to claim 1, it is characterized in that: the Pharmaceutical composition that contains indinavir and valproic acid or its salt is based on 100% of gross weight, contain: the 1. indinavir of 0.1-95%, 2. the valproic acid of 1-95% or its salt, 3. the diluent of 0-35%, 4. the binding agent of 0-20%, 5. 6. lubricant and 7. other pharmaceutically acceptable coloring agent and/or correctivess of 0～10% of 0-10% of 0-30% disintegrating agent.
4. the Pharmaceutical composition that contains indinavir and valproic acid or its salt according to claim 1 is characterized in that: diluent comprises one or more in lactose, sucrose, mannitol, sorbitol, starch, pregelatinized Starch, cellulose, processing agar, glucose, dicalcium phosphate, calcium hydrogen phosphate, gelatin or the dextrin.
5. the Pharmaceutical composition that contains indinavir and valproic acid or its salt according to claim 1 is characterized in that: binding agent comprises the water of one or more adjuvants in water, ethanol, tween 80, polyvinylpyrrolidone (PVP), methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium alginate, aluminium-magnesium silicate, arabic gum or the Polyethylene Glycol or the solution of alcohol.
6. the Pharmaceutical composition that contains indinavir and valproic acid or its salt according to claim 1 is characterized in that: disintegrating agent comprises one or more in carboxymethyl starch sodium (CMS-Na), crosslinked carboxymethyl fecula sodium (cCMS-Na), low-substituted hydroxypropyl cellulose (LHPC), crospolyvinylpyrrolidone (PVPP), AmberliteIRP-88, sodium carboxymethyl cellulose (CMC-Na), cross-linking sodium carboxymethyl cellulose (cCMC-Na), carboxymethylcellulose calcium or the microcrystalline Cellulose (MCC).
7. the Pharmaceutical composition that contains indinavir and valproic acid or its salt according to claim 1, it is characterized in that: lubricant comprises one or more in magnesium stearate, calcium stearate, stearic acid, Polyethylene Glycol, silicon dioxide, micropowder silica gel, Pulvis Talci, aluminium hydroxide, alginic acid, natural gum or the Stepanol MG.
8. the Pharmaceutical composition that contains indinavir and valproic acid or its salt according to claim 1 is characterized in that: pharmaceutically acceptable coloring agent of used other and correctives comprise red, red scarlet, the light blue of coloring agent lemon yellow, sunset yellow, carmine, amaranth, temptation, indigo, light green, egg yolk and medicinal color lake and correctives A Siba is sweet, in glycyrrhizin, stevioside, saccharin sodium or the medicinal essence one or more.
9. the Pharmaceutical composition that contains indinavir and valproic acid or its salt according to claim 1 is characterized in that: valproic acid and salt thereof comprise valproic acid, sodium valproate, magnesium valproate, valproic acid calcium or derivant valpromide.
10. the Pharmaceutical composition that contains indinavir and valproic acid or its salt according to claim 1 is characterized in that: indinavir also comprises its pharmaceutically acceptable indinavir sulfate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510086717 CN1792363A (en) | 2005-10-26 | 2005-10-26 | Medicinal composition contg. IDV and valproic acid or salts thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510086717 CN1792363A (en) | 2005-10-26 | 2005-10-26 | Medicinal composition contg. IDV and valproic acid or salts thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1792363A true CN1792363A (en) | 2006-06-28 |
Family
ID=36804136
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510086717 Pending CN1792363A (en) | 2005-10-26 | 2005-10-26 | Medicinal composition contg. IDV and valproic acid or salts thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1792363A (en) |
-
2005
- 2005-10-26 CN CN 200510086717 patent/CN1792363A/en active Pending
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