CN1822822B - Saquinavir mesylate oral dosage form - Google Patents
Saquinavir mesylate oral dosage form Download PDFInfo
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- CN1822822B CN1822822B CN200480019933.XA CN200480019933A CN1822822B CN 1822822 B CN1822822 B CN 1822822B CN 200480019933 A CN200480019933 A CN 200480019933A CN 1822822 B CN1822822 B CN 1822822B
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- dosage form
- saquinavir
- saquinavir mesylate
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- mesylate
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- IRHXGOXEBNJUSN-YOXDLBRISA-N Saquinavir mesylate Chemical compound CS(O)(=O)=O.C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 IRHXGOXEBNJUSN-YOXDLBRISA-N 0.000 title claims abstract description 64
- 229960003542 saquinavir mesylate Drugs 0.000 title claims abstract description 64
- 239000006186 oral dosage form Substances 0.000 title description 4
- 239000002552 dosage form Substances 0.000 claims abstract description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000007787 solid Substances 0.000 claims abstract description 15
- 239000011230 binding agent Substances 0.000 claims abstract description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000008187 granular material Substances 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 32
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 239000003513 alkali Substances 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 22
- 239000002775 capsule Substances 0.000 claims description 17
- 229960001852 saquinavir Drugs 0.000 claims description 15
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 claims description 15
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 14
- 239000000314 lubricant Substances 0.000 claims description 14
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 14
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 14
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 11
- 238000009501 film coating Methods 0.000 claims description 10
- 239000007888 film coating Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- 239000000853 adhesive Substances 0.000 claims description 7
- 230000001070 adhesive effect Effects 0.000 claims description 7
- 238000005469 granulation Methods 0.000 claims description 7
- 230000003179 granulation Effects 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 7
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 6
- 238000009478 high shear granulation Methods 0.000 claims description 6
- 229960001021 lactose monohydrate Drugs 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 5
- 238000004132 cross linking Methods 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 5
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 5
- 239000007921 spray Substances 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000012052 hydrophilic carrier Substances 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 238000000227 grinding Methods 0.000 claims 1
- 239000007884 disintegrant Substances 0.000 abstract description 3
- 239000003232 water-soluble binding agent Substances 0.000 abstract description 2
- 239000012458 free base Substances 0.000 abstract 1
- 239000007892 solid unit dosage form Substances 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 25
- 238000004090 dissolution Methods 0.000 description 16
- 229920003081 Povidone K 30 Polymers 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 241000725303 Human immunodeficiency virus Species 0.000 description 5
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 239000008109 sodium starch glycolate Substances 0.000 description 5
- 229940079832 sodium starch glycolate Drugs 0.000 description 5
- 229920003109 sodium starch glycolate Polymers 0.000 description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 239000007963 capsule composition Substances 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[(2r,3s,4r,5r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical class O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 description 2
- KMZHZAAOEWVPSE-UHFFFAOYSA-N 2,3-dihydroxypropyl acetate Chemical compound CC(=O)OCC(O)CO KMZHZAAOEWVPSE-UHFFFAOYSA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- 230000000798 anti-retroviral effect Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229940031705 hydroxypropyl methylcellulose 2910 Drugs 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 150000003833 nucleoside derivatives Chemical class 0.000 description 2
- -1 polyethylene Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 235000021152 breakfast Nutrition 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 230000009246 food effect Effects 0.000 description 1
- 235000021471 food effect Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 235000019602 lubricity Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
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- 238000011179 visual inspection Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A solid unit oral pharmaceutical dosage form of saquinavir mesylate is provided comprising micronized saquinavir mesylate in an amount of from 250 mg to 800 mg calculated as free base, and a pharmaceutically acceptable binder, disintegrant, and water soluble carrier. A solid unit dosage form of saquinavir mesylate is provided comprising from 60% to 80% micronized saquinavir mesylate based on the mesylate salt, 4% to 8% water soluble binder, a disintegrant and a carrier, wherein each percentage is of the kernel weight.
Description
Saquinavir mesylate (Saquinavir mesylate) is to be used for duplicating and improving one of several protease inhibitor of immunologic function at infected by HIV individuality limiting virus.The saquinavir mesylate commodity of existing 200mg capsule (pressing the Saquinavir free alkali calculates) form.These commodity by Hoffmann-La Roche Inc. with trade name
Sell, and show that it can infect with the HIV (human immunodeficiency virus) in late period (HIV) for the treatment of selected patient with the coupling of antiretroviral nucleoside analog.
Saquinavir mesylate is an extremely cream-coloured very fine crystalline, powder of white, and molecular weight is 766.96.Its free alkali molecular weight is 670.86.This medicine height is hydrophobic.
The capsular oral administration biaavailability of (saquinavir mesylate) 200mg is low, this be considered to since its not exclusively absorb and widely first pass metabolism cause.[Physician ' s Desk Reference, the 57th edition.(2003)]。Saquinavir mesylate have low-down water solubility (promptly in the time of 25 ℃ in water dissolubility be 2.2mg/mL, in simulated gastric fluid dissolubility be 0.08mg/mL, almost insoluble in simulated intestinal fluid).In addition, this medicine presents the dissolution characteristics that pH relies on: dissolubility is limited then almost insoluble in simulated intestinal fluid in simulated gastric fluid.Accepting a 600mg dosage (3 * 200mg capsule) Saquinavir and eating subsequently among 8 healthy volunteers of higher fatty acid breakfast, (CV 73%, scope: 1-9%) for absolute bioavailability average out to 4%.24 hours AUC values of Saquinavir after the edible more high heat food and cmax value (n=6) than edible food more low in calories after the average twice of height.The effect that has shown food continues more than two hours.For with the difference between the experimenter and in human body being seen saquinavir mesylate food effect minimize, need a kind of the have homogeneous and the oral dosage form of saquinavir mesylate dissolution fast.
Reducing granular size is a kind of method that experimenter's differences is minimized and improve bioavailability.Micronization is the method that is used to reduce granular size.But saquinavir mesylate is tending towards agglomerating when micronization, thereby has reduced the surface area that its primary granule contacts with dissolve medium.Micronized saquinavir mesylate presents low dissolution rate.
For the adult patient, with the nucleoside analog coupling
Recommended dose is 3 * 200mg capsule, every day three times and taking in 2-4 hour after the meal.Given this dosage, real what worry is patient's compliance.Encourage patient to defer to better and can improve the treatment success rate, similarly can also can improve the treatment success rate by the quantity of the dosage unit that for example reduces every day and must take.Therefore it will be very useful comprising more the unit dosage forms of a large amount Saquinavir.But along with the increase of micronization saquinavir mesylate drug loading, medicine becomes clique problem more serious.
The invention provides the solid unit oral Pharmaceutical dosage forms of saquinavir mesylate, this dosage form comprises about 60% to about 80% the micronization saquinavir mesylate based on mesylate, about 4% to about 8% pharmaceutically acceptable water soluble adhesive, pharmaceutically acceptable disintegrating agent and pharmaceutically suitable carrier, and wherein each percent is to account for the heavy percent of pharmaceutical dosage form nuclear core.(about 60% to about 80% micronization saquinavir mesylate is equivalent to the amount with the extremely about 800mg saquinavir mesylate of about 200mg of Saquinavir free alkali calculating).
In preferred embodiments, saquinavir mesylate is approximately the heavy 70%-75% of solid unit oral Pharmaceutical dosage forms nuclear core.
The invention provides the solid unit oral Pharmaceutical dosage forms of saquinavir mesylate, it comprises micronization saquinavir mesylate, pharmaceutically acceptable binding agent, pharmaceutically acceptable disintegrating agent and the pharmaceutically acceptable water solubleness carrier of the extremely about 800mg amount of the about 250mg that calculates with free alkali.
The accompanying drawing summary
Fig. 1 shows the dissolution of Tabules preparation of the present invention (embodiment 1 (500mg free alkali)), shows a batch repeatability.
Fig. 2 shows the dissolution of current market capsule formulation preparation (embodiment 2 (200mg free alkali)), shows a batch diversity.
Fig. 3 shows that the Tabules preparation of the present invention (embodiment 1) and the dissolution of the current market capsule formulation preparation (embodiment 2) of 1000mg Saquinavir free alkali dosage compare.
Fig. 4 shows that the capsule formulation preparation of the present invention (embodiment 3) and the dissolution of the current market capsule formulation preparation (embodiment 2) of 1000mg Saquinavir free alkali dosage compare.
Fig. 5 shows the dissolution of Tabules preparation of the present invention (embodiment 1 (500mg Saquinavir free alkali)), shows no matter used press power is as what having fast and the dissolution of high performance reproducibility.
Fig. 6 shows that the Tabules preparation of the present invention (embodiment 1) and the dissolution of the conventional tablet preparation (embodiment 4) of 1000mg Saquinavir free alkali dosage compare.
Fig. 7 shows the dissolution of Tabules preparation of the present invention (embodiment 1 (500mg free alkali)), shows no matter the granulation terminal point is as what having fast and the dissolution of high performance reproducibility.
Provide fast and dissolution rate highly repeatably according to micronizing saquinavir mesylate pharmaceutical dosage form of the present invention. Saquinavir mesylate formulation of the present invention can be used for the treatment of the individuality that HIV infects. Considered to use simultaneously with other antiretroviral drugs (such as Ritonavir).
The invention provides the solid unit oral Pharmaceutical dosage forms of saquinavir mesylate, described formulation comprises about 200mg of calculating with the Saquinavir free alkali to approximately 800mg, preferred 200mg-700mg, more preferably 250mg-700mg even the more preferably micronizing saquinavir mesylate of 500mg amount.
The solid unit oral Pharmaceutical dosage forms of saquinavir mesylate also comprises pharmaceutically suitable carrier, this carrier be preferably water miscible and its weight be about the nuclear core heavy about 3% to about 10%, 4%-6% preferably approximately. Water-solubility carrier has about 30 microns to 200 microns granular size easily. Preferred water-solubility carrier is to have about 100 microns lactose monohydrates to 150 micron particles sizes.
Pharmaceutically acceptable water soluble adhesive content is about the heavy 4%-8% of nuclear core, preferred about 4%-6%.Preferred water-soluble binder is a polyvinylpyrrolidone.The fit closely polyvinylpyrrolidone that is commodity polyvidone (Povidone) by name as 30 POVIDONE K 30 BP/USP 30.
Pharmaceutically acceptable disintegrant content is about the heavy 3%-10% of nuclear core, preferred about 4%-8%.Preferred pharmaceutically acceptable disintegrating agent can be selected from that cross-linked carboxymethyl cellulose is received and polyvinylpolypyrrolidone (cropovidone).
Preparation saquinavir mesylate, carrier, binding agent and to the granule of small part disintegrating agent.This granule is made up of saquinavir mesylate, carrier, binding agent and the disintegrating agent agglomerate thing of variable grain size, but and gained powder free-flow and have favourable compaction characteristics and moisture performance.When unit dose was tablet, then tablet was partly by these agglomerate thing preparations.When tablet was exposed to gastro-intestinal Fluid, disintegrate took place and discharges the micronization saquinavir mesylate so that stripping fast in it.
After being prepared into granule, microcrystalline Cellulose (MCC) can be added wherein to strengthen the mechanical strength of the tablet of being produced as the outer component of granule.MCC content can be easily be the heavy about 5%-20% of nuclear core, 5%-15% preferably approximately.
Lubricant such as magnesium stearate can be added with the outer component form of granule, its weight is approximately the heavy 0.5%-1.2% of nuclear core.
The present invention also provides the method for preparing saquinavir mesylate solid unit oral Pharmaceutical dosage forms.This method comprises with disintegrating agent and hydrophile adhesive mass and carrier makes medicine form microparticle.Therefore the saquinavir mesylate that is still keeping crystal form in the dosage form of being produced.
Compare with currently marketed capsule preparations, preparation of the present invention (no matter being tablet or capsule) all shows faster relatively and repeatable good dissolution degree.In addition, disclosed peroral dosage form provides fast and the dissolution of high performance reproducibility in the literary composition, and no matter press power and granulation terminal point how.Dosage form of the present invention advantageously has the weight of about 400mg to 1.5g.
Solid unit oral Pharmaceutical dosage forms of the present invention comprises the nuclear core and holds the part of examining core.According to the present invention, this nuclear core comprises saquinavir mesylate, binding agent, disintegrating agent and carrier.This nuclear core randomly comprises one or more pharmaceutically acceptable excipient, for example lactose monohydrates.This nuclear core preferably is made up of granule and the mixture that joins the excipient (" the outer component of granule ") in the granule.Hold the part of examining core and can be the capsule shells of tablet thin film coating for example or capsule or scrotiform tablet (caplet).
The used saquinavir mesylate of the present invention becomes little granular size through micronization.The micronization saquinavir mesylate generally is the saquinavir mesylate of granule between about 1 micron to 20 microns.In preparation solid unit oral Pharmaceutical dosage forms, the amount of employed micronization saquinavir mesylate with mesylate be calculated as the nuclear core heavy about 60% to about 80%.This is equivalent to the micronization saquinavir mesylate with the extremely about 800mg of about 200mg of Saquinavir free alkali calculating.
The optional pharmaceutically acceptable excipient that uses of the present invention comprises the excipient type except that those described excipient.Therefore, the percent of binding agent and disintegrating agent is still keeping specified level in the nuclear core.The pharmaceutically acceptable excipient that can choose use wantonly comprises microcrystalline Cellulose and lubricant.
Lubricant comprises for example magnesium stearate and Pulvis Talci.Preferred magnesium stearate.Lubricant can be as the outer component of the granule of nuclear core.Lubricant content is preferably the heavy 0.5%-1.2% of nuclear core.
Join through grind, excipient in the dried granules can be lubricant, disintegrating agent and diluent.Drug excipient can be for example microcrystalline Cellulose, corn starch, magnesium stearate etc.In order to prepare tablet, can be by granulating, grind, mix, lubricate, suppress (being pressed into tablet) and typical water film coating being processed into the solid unit peroral dosage form with solid dosage forms.
By with the micronization saquinavir mesylate with disintegrating agent and hydrophilic adhesive and carrier micronizing and grind to handle and prepare pharmaceutical dosage form of the present invention.Preferably, with granule and mix lubricant, be pressed into tablet and carry out the water film coating.In the micronizing process, micronized saquinavir mesylate is gone agglomerating processing, and make it moistening with hydrophilic carrier and binding agent, thus the maximization of the surface area of the feasible primary granule that contacts with dissolve medium.
The invention provides the method for preparing micronization saquinavir mesylate solid unit oral Pharmaceutical dosage forms, it comprises spray water soluble adhesive solution on the mixture of the extremely about 800mg micronization saquinavir mesylate of the about 200mg that calculates with free alkali, pharmaceutically acceptable disintegrating agent and pharmaceutically acceptable water solubleness carrier, to obtain homogeneous granule of the present invention.Preferably, carrier is a lactose monohydrate, and disintegrating agent is that cross-linked carboxymethyl cellulose is received.
Preferably, a part of disintegrating agent can be contained in the granule, and the disintegrating agent of remainder is added and mixes as the outer component of granule.The ratio of the disintegrating agent in the outer component of disintegrating agent in the granule and granule was from about 3: 1 to about 1: 1.Preferably, this ratio was from about 2.5: 1 to about 1.5: 1.More preferably, this ratio is about 2: 1.
Preferably, microcrystalline Cellulose adds and mixes to strengthen the mechanical strength of gained tablet with granule as the outer component of granule.Microcrystalline Cellulose account for the nuclear core heavy about 5% to about 20%, preferably approximately 5% to about 15%.
Preferably, will join particulate outside, so that when compacting, enough lubricities are provided for tablet stamping machine equipment such as the lubricant of magnesium stearate.Lubricant account for nuclear core heavy about 0.5% to about 1.2%.
In embodiments of the invention, be prepared as follows tablet:
A) in the high-shear granulation machine, the micronization saquinavir mesylate is mixed with hydrophilic carrier and disintegrating agent with the amount of the extremely about 800mg of the about 200mg of per unit dosage (calculating with free alkali).
B) also mix simultaneously to the mixture of powders sprinkling of step (a) or the binder aqueous solution that slowly is incorporated in the water, to reach best granulation terminal point.
C) wet granular of step (b) is gone agglomerate handle to make and become the homogeneous granule.
D) in being set to the fluidized bed dryer that 40 ℃-50 ℃ pressure air-oven (forced air oven) or inlet air temperature be 50 ℃-60 ℃ with the wet grain drying of step (c), up to particulate moisture in the 1.5%-2% scope.
E) dried particles with step (d) grinds.
F) grind granule and other suitable tablet diluent such as microcrystalline Cellulose and disintegrating agent of step (e) are mixed.
G) lubricate the mixture of step (f) with suitable lubricant such as magnesium stearate.
H) on tablet machine that the final mixture compacting of step (g) is in blocks.
I) sheet with step (h) carries out the aqueous film coating.
Embodiment
In the following example, but the terminal point when by visual inspection granular size being no longer included change detected is defined as best granulation terminal point.
Embodiment 1
Table 1:500mg saquinavir mesylate tablet (preparation of the present invention)
| Composition | The mg/ sheet |
| The micronization saquinavir mesylate | 571.50 ＊ |
| Lactose monohydrate | 38.50 |
| Cross-linked carboxymethyl cellulose is received | 45.00 |
| 30 POVIDONE |
40.00 |
| Microcrystalline Cellulose (Avicel PH 101) | 95.00 |
| Magnesium stearate | 10.00 |
| Sheet heart weight | 800.00 |
| Hydroxypropyl methylcellulose 2910 (6cps) | 7.01 |
| Titanium dioxide | 4.32 |
| Pulvis Talci | 4.32 |
| Composition | The mg/ sheet |
| Yellow iron oxide | 0.57 |
| Red iron oxide | 0.08 |
| Ethylcellulose dispersion (solid) | 2.32 |
| Acetin | 1.38 |
| Gross weight | 820.00 |
*Be equivalent to the 500mg free alkali
I. sheet heart preparation
A. in the high-shear granulation machine, micronization saquinavir mesylate, lactose monohydrate and a part of cross-linking sodium carboxymethyl cellulose (be approximately cross-linking sodium carboxymethyl cellulose total amount 66.7%) were mixed 5 minutes with low speed impeller and low-speed agitator.
B. prepare 20% (w/w) 30 POVIDONE K 30 BP/USP, 30 solution: in rustless steel container, 30 POVIDONE K 30 BP/USP 30 is joined (160mg/ sheet) in the pure water lentamente, and mix with propeller mixer.Mix and last till that 30 POVIDONE K 30 BP/USP 30 dissolves fully.
C. (1). in the high-shear granulation machine, spray 20% (w/w) 30 POVIDONE K 30 BP/USP, 30 solution of step B, this mixture of powders is granulated, and continue mixing above 8-10 minute with low speed impeller and low-speed agitator to the mixture of powders of steps A.
C. (2). to the extra pure water (approximately 180mg/ sheet) of mixture of powders sprinkling that continues to mix step C (1) gained that surpasses 8-10 minute with low speed impeller and low-speed agitator.This granule is carried out extra kneading to be handled to reach best granulation terminal point.This wet granular is pushed in the container of polyethylene lining with low speed impeller and low-speed agitator.
D. with wet granular through 1350 rev/mins Co-mil that has 19.05-mm round-hole mesh (#750Q) or 1000-2000 rev/min the Frewitt rotary screen that has the 10-mm round-hole mesh, make this wet granular remove agglomerate.
E. remove the agglomerate wet granular what inlet air temperature was set to drying steps D in 65 ℃ ± 10 ℃ the fluidized bed dryer, moisture is lower than 1.8% in the weightless determined granule until be set to 90 ℃ Omnimark moisture analyzer drying by use after.
F. with the dried particles of step e by 4500 rev/mins have the Co-mil 1.27-mm circle, that grind hole sizer (#050G) or cutter pace be 3170 rev/mins the Frewitt tup formula grater that has the 2.0-mm round-hole mesh, this dried particles is ground.
G. in PK agitator or equivalent instrument, the cross-linking sodium carboxymethyl cellulose that grinds granule and Avicel PH 101 and remainder of step F (be approximately cross-linking sodium carboxymethyl cellulose total amount 33.3%) was mixed 10 minutes.
H. the granule with about 50% in the PK agitator of step G shifts out.
I. in the PK of step H agitator, add magnesium stearate (having passed through the stainless steel sift of #30 mesh).Put back to the granule that shifts out among the step H in the PK agitator and mixed 5 minutes.
J. by following specification the granule of step I is pressed into tablet:
Dash size: ellipse, 8.74mm * 18.75mm, standard concave
Tablet weight: 800mg (760-840mg)
Tablet hardness: 30SCU (25-35SCU) or 210N (175-245N)
II. film coating
A.
Preparation film coating suspension
In rustless steel container, acetin and Aquacoat AquacoatECD-30 are scattered in the pure water with propeller mixer, and mixed 45 minutes.
The mixture of powders that adds hydroxypropyl methylcellulose 2910 (6cps), Pulvis Talci, titanium dioxide, yellow iron oxide and red iron oxide in this dispersion mixes gently to avoid producing air entrapment.Continue to mix again 60 minutes or until obtaining the homogeneous suspension.
B.
Film coating
The sheet heart of part I (preparation of the sheet heart) step J gained is inserted in the porose coating pan.Inlet temperature is slowly risen to 60 ℃ ± 10 ℃ heating this sheet heart, and jolt discontinuously, reach 40 ℃ ± 5 ℃ until outlet temperature.
When inlet air temperature is 60 ℃ ± 10 ℃, increase pot speed so that the interior sheet heart of pot fully rotates.Spray above-mentioned part IIA prepared film coating suspension to the sheet heart, and stir continuously with the air spray system.Product temperature maintains 45 ℃ ± 5 ℃.Dry basis, every is used 20mg film coating (scope 17-23mg).
Inlet air temperature is reduced to 50 ℃ ± 5 ℃ and with pot prompt drop to 4 ± 2 rev/min.The dry run of coated tablet continues 2-4 minute.
Inlet air temperature is reduced to 40 ℃ ± 5 ℃, and makes the coated tablet drying by jolting, weightless determined tablet moisture content is lower than 2.0% until be set to 90 ℃ Omnimark moisture analyzer drying by use after.Close heater, and tablet is cooled to room temperature by jolting once in a while.
Embodiment 2
Table 2:200mg saquinavir mesylate capsule (market preparation)
| Composition | The mg/ capsule |
| The micronization saquinavir mesylate | 228.70 ＊ |
| Sodium starch glycolate | 16.00 |
| Lactis Anhydrous | 63.30 |
| Microcrystalline Cellulose (Avicel PH102) | 60.00 |
| 30 |
8.00 |
| Magnesium stearate | 4.00 |
| Pulvis Talci | 28.00 |
| Loading | 408.00 |
| Capsule shells (big or small #0) | 96.00 |
| Composition | The mg/ capsule |
| Gross weight | 504.00 |
*Be equivalent to the 200mg free alkali
A. in the high-shear granulation machine, micronization saquinavir mesylate, Lactis Anhydrous, microcrystalline Cellulose and a part of sodium starch glycolate (sodium starch glycolate total amount 56.25%) are mixed.
B. the mixture of powders in the high-shear granulation machine (steps A) adds 30 POVIDONE K 30 BP/USP 30 solution and continues mixing, and this mixture of powders is granulated.
C. in the mixture of powders of step B, add extra pure water, and continue to mix until obtaining best granulation terminal point.The gained wet granular is pushed in the container of polyethylene lining.
D. the wet granular with step C makes it agglomerate by grater.
E. inlet air temperature be set in 65 ℃ ± 10 ℃ the fluidized bed dryer with step D remove the agglomerate wet grain drying, weightless determined pellet moisture content is lower than 1.8% until be arranged to 90 ℃ Omnimark moisture analyzer drying by use after.
F. the dried particles with step e passes through grater.
G. in agitator, grind granule and a part of sodium starch glycolate (sodium starch glycolate total amount 43.75%), Pulvis Talci and the magnesium stearate of step F are mixed.
H. with capsule filling machine the final mixture of step G is filled and enter capsule (#0), the target loading is 408mg.
Embodiment 3
Table 3:200mg saquinavir mesylate capsule (preparation of the present invention)
| Composition | The mg/ capsule |
| The micronization saquinavir mesylate | 228.70 ＊ |
| Lactose monohydrate | 15.30 |
| Cross-linked carboxymethyl cellulose is received | 18.00 |
| 30 |
16.00 |
| Microcrystalline Cellulose (Avicel PH101) | 38.00 |
| Magnesium stearate | 4.00 |
| Loading | 320.00 |
| Capsule shells (big or small #0) | 96.00 |
| Gross weight | 416.00 |
*Be equivalent to the 200mg free alkali
For steps A-I, with the method for embodiment 1 detailed description.
Step J. fills the final mixture of step I gained with capsule filling machine and enters capsule (#0), and the target loading is 320mg.
Table 4: with the 500mg saquinavir mesylate tablet of previous method production
| Composition | The mg/ sheet |
| The micronization saquinavir mesylate | 571.50 ＊ |
| 30 |
20.00 |
| Lactis Anhydrous | 158.25 |
| Microcrystalline Cellulose (Avicel PH102) | 150.00 |
| Sodium starch glycolate | 40.00 |
| Pulvis Talci | 70.00 |
| Sodium stearate | 10.00 |
| The tablet total weight amount | 1019.75 |
*Be equivalent to the 500mg free alkali
For steps A-G, with the method for embodiment 2 detailed descriptions.
Step H. is pressed into tablet by following specification with the granule of step G:
Dash size: ellipse, 9.28mm * 20.02mm, standard concave
Tablet weight: 1200mg (1140-1260mg)
Tablet hardness: 25-35SCU or 175-245N
The dissolution test:
Use oar method (USPApparatus 2) to be to measure in 37 ℃ ± 0.5 ℃ equilibrated 900mL citrate buffer (pH3.0) dissolution that comprises Saquinavir mesylate oral dosage form (embodiment 1-4) with 50 rev/mins rotating speeds.The aliquot of taking out sample at interval at different time, and analyze with ultraviolet spectrophotometry.
Claims (18)
1. saquinavir mesylate solid unit oral Pharmaceutical dosage forms, described dosage form comprise 60% to 80% have 1 micron micronization saquinavir mesylate, 4% to 8% polyvinylpyrrolidone based on mesylate to 20 micron particle sizes as the lactose monohydrate of pharmaceutically acceptable water soluble adhesive, 3% to 10% pharmaceutically acceptable disintegrating agent and 3% to 10% as the pharmaceutically acceptable water solubleness carrier, wherein said each percent is to account for the heavy percent of this pharmaceutical dosage form nuclear core.
2. dosage form according to claim 1, wherein saquinavir mesylate account for pharmaceutical dosage form nuclear core heavy 70% to 75%.
3. dosage form according to claim 1 and 2, wherein the amount of saquinavir mesylate is calculated as 200mg to 700mg with the Saquinavir free alkali in described pharmaceutical dosage form.
4. according to the described dosage form of claim 1-3, wherein the amount of saquinavir mesylate is calculated as 250mg to 700mg with the Saquinavir free alkali in described pharmaceutical dosage form.
5. according to the described dosage form of claim 1-4, wherein the amount of saquinavir mesylate is calculated as 500mg with the Saquinavir free alkali in described pharmaceutical dosage form.
6. dosage form according to claim 1, wherein lactose monohydrate has 100 microns to 150 microns granular size.
7. dosage form according to claim 1, wherein disintegrating agent is selected from cross-linking sodium carboxymethyl cellulose and polyvinylpolypyrrolidone.
8. dosage form according to claim 1, it also comprises microcrystalline Cellulose.
9. dosage form according to claim 8, wherein microcrystalline Cellulose account for nuclear core heavy 5% to 20%.
10. dosage form according to claim 1, wherein dosage form also comprises lubricant.
11. dosage form according to claim 10, wherein lubricant is a magnesium stearate.
12. dosage form according to claim 1, wherein the nuclear core of pharmaceutical dosage form is made up of the mixture of granule and the outer component of granule, wherein said granule comprises micronization saquinavir mesylate, binding agent, carrier and disintegrating agent, and the outer component of granule comprises disintegrating agent, and wherein the ratio of the disintegrating agent in the outer component of disintegrating agent in the granule and granule is 3: 1 to 1: 1.
13. dosage form according to claim 12, it also contains the lubricant in the outer component of the granule that is contained in the nuclear core.
14. according to the described dosage form of claim 1-13, it is selected from tablet, capsule and scrotiform tablet.
15. according to the described dosage form of claim 1-14, it has the weight of 400mg to 1.5g.
16. according to the described solid unit oral Pharmaceutical dosage forms of claim 1-15, wherein saquinavir mesylate is a crystalline form.
17. preparation is according to the method for the described solid unit oral Pharmaceutical dosage forms of claim 1-16; this method comprises that the mixture with micronization saquinavir mesylate, pharmaceutically acceptable water soluble adhesive, pharmaceutically suitable carrier and medical active disintegrating agent carries out micronizing, and grinding subsequently.
18. method according to claim 17 comprises step:
A) in the high-shear granulation machine, the micronization saquinavir mesylate is mixed with hydrophilic carrier and disintegrating agent with the amount of calculating per unit dosage 200mg to 700mg according to the Saquinavir free alkali,
B) spray or slowly be incorporated in the binder aqueous solution in the water and mix simultaneously to step (a) gained mixture of powders, reaching best granulation terminal point,
C) wet granular with step (b) goes the agglomerate processing and becomes the homogeneous granule,
D) in being set to the fluidized bed dryer that 40 ℃-50 ℃ pressure air-oven or inlet air temperature be 50 ℃-60 ℃ with the wet grain drying of step (c), up to particulate moisture in the 1.5%-2% scope,
E) dried particles with step (d) grinds,
F) granule that grinds with step (e) mixes with suitable tablet diluent,
G) use suitable lubricant to lubricate the mixture of step (f),
H) on tablet machine with the compacting of the final mixture of step (g) in flakes and
I) sheet with step (h) carries out the aqueous film coating.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US48660003P | 2003-07-11 | 2003-07-11 | |
| US60/486,600 | 2003-07-11 | ||
| US56820404P | 2004-05-05 | 2004-05-05 | |
| US60/568,204 | 2004-05-05 | ||
| PCT/EP2004/007309 WO2005004836A2 (en) | 2003-07-11 | 2004-07-05 | Saquinavir mesylate oral dosage form |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1822822A CN1822822A (en) | 2006-08-23 |
| CN1822822B true CN1822822B (en) | 2010-06-16 |
Family
ID=36923757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200480019933.XA Expired - Lifetime CN1822822B (en) | 2003-07-11 | 2004-07-05 | Saquinavir mesylate oral dosage form |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1822822B (en) |
| GT (1) | GT200400131A (en) |
| UA (1) | UA81335C2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104096216B (en) * | 2014-07-08 | 2016-03-09 | 滨州医学院 | Methanesulfonic acid Sha Kuilawei prevents in preparation or treats the application in the medicine of ischemic cardio cerebrovascular diseases |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999012527A2 (en) * | 1997-09-09 | 1999-03-18 | Alza Corporation | Dosage form comprising means for changing drug delivery shape |
| US6039975A (en) * | 1995-10-17 | 2000-03-21 | Hoffman-La Roche Inc. | Colon targeted delivery system |
| WO2003005944A1 (en) * | 2001-07-10 | 2003-01-23 | Cima Labs Inc. | Sequential drug delivery systems |
-
2004
- 2004-05-07 UA UAA200601231A patent/UA81335C2/en unknown
- 2004-07-05 CN CN200480019933.XA patent/CN1822822B/en not_active Expired - Lifetime
- 2004-07-08 GT GT200400131A patent/GT200400131A/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6039975A (en) * | 1995-10-17 | 2000-03-21 | Hoffman-La Roche Inc. | Colon targeted delivery system |
| WO1999012527A2 (en) * | 1997-09-09 | 1999-03-18 | Alza Corporation | Dosage form comprising means for changing drug delivery shape |
| WO2003005944A1 (en) * | 2001-07-10 | 2003-01-23 | Cima Labs Inc. | Sequential drug delivery systems |
Also Published As
| Publication number | Publication date |
|---|---|
| GT200400131A (en) | 2005-02-22 |
| UA81335C2 (en) | 2007-12-25 |
| CN1822822A (en) | 2006-08-23 |
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