CN101224211A - Entecavir solid dispersoid, medicine compounds and preparing method and applications thereof - Google Patents

Entecavir solid dispersoid, medicine compounds and preparing method and applications thereof Download PDF

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CN101224211A
CN101224211A CNA2008100032990A CN200810003299A CN101224211A CN 101224211 A CN101224211 A CN 101224211A CN A2008100032990 A CNA2008100032990 A CN A2008100032990A CN 200810003299 A CN200810003299 A CN 200810003299A CN 101224211 A CN101224211 A CN 101224211A
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entecavir
sodium
solid dispersion
carrier material
polyethylene glycol
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CN101224211B (en
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杨喜鸿
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Abstract

The invention relates to a solid dispersion containing entecavir and any one or more components of polyethylene glycol, glycerin monostearate, polyoxyl stearate, sucrose ester of fatty acid and polyoxyethylenated castor oil and well overcomes the shortages of poor water solubility and dissolution of entecavir and is beneficial for the preparation of the medicine preparation and improving medicine quality. The invention also relates to the preparation, the medicine combination and the medicine application of the solid dispersion containing the entecavir and the carrier materials.

Description

The solid dispersion of Entecavir, pharmaceutical composition and preparation method thereof and medicinal application
Technical field the invention belongs to the pharmaceutical technology field, relate to Entecavir solid dispersion, pharmaceutical composition, and preparation method thereof, further also related to the application of this solid dispersion in pharmaceutical preparation.
Background technology Entecavir (Entecavir) is a kind of guanosine analog, and chemical name is 2-amino-9-[(1S, 3R, 4S)-and 4-hydroxyl-3-methylol-2-methylene cyclopenta]-1,9-dihydro-6H-purine-6-one, molecular structural formula is as follows:
Figure S2008100032990D00011
, molecular formula C 12H 15N 5O 3, molecular weight 277.3 contains a water of crystallization usually, its monohydrate molecular formula C 12H 15N 5O 3H 2O, molecular weight 295.3.
U.S. Pat 5,206,244 disclose Entecavir and its purposes at the treatment hepatitis B.International publication WO98/09964 and WO2004/052310 disclose the synthetic method of two kinds of Entecavirs that improved respectively.U.S. Patent application US-2001-0033864-A1 and PCT patent application WO01/64421A1 disclose the preparation compositions that contains the low dosage Entecavir.
Entecavir is a kind of antiviral agent efficiently, clinical research has shown the hepatitis B virus good inhibition effect, because the activity of Entecavir anti-hepatitis virus is very high, low-down dosage just is enough to reach the desired therapeutic effect, generally be grown up every day oral 0.5mg or the 1mg Entecavir can reach good therapeutical effect.
The pharmaceutical preparation of the Entecavir of listing is oral common gastric solubleness dosage form both at home and abroad at present, as tablet and oral liquid, feed can cause the delay to the Entecavir absorption, and then cause malabsorption and declined bioavailability of oral administration, therefore should the oral (Entecavir sheet/Bo Luding of empty stomach when using this type of common gastric solubleness dosage form TMDescription requires), at least before the meal or latter two hour of eating take just and can reach drug absorption preferably.
Entecavir is as the active ingredient of medicine, when it is made as medicinal preparation for oral administration, having only Entecavir to be dissolved in fast and efficiently or to be scattered in the water could absorb in gastrointestinal well, otherwise, absorption and biological utilisation for it have very big obstacle, therefore, the physical property of improvement Entecavir makes it be dissolved in fast and efficiently or to be scattered in the water, is very important and significant.
Summary of the invention is vital because therefore the poorly water-soluble of Entecavir under the prerequisite that does not change its chemical compound pharmacological properties, improves its water solublity and dissolution.
The inventor is by studying and putting into practice pleasantly surprisedly and find: adopt the suitable carriers material that Entecavir is made solid dispersion, can improve the dissolubility of Entecavir in water well, the water-soluble of Entecavir is significantly improved.And within the specific limits, along with the amount increase of carrier material, the dissolubility of Entecavir also can further improve.
Based on above research and practice, the invention provides the technology contents of following aspect:
First aspect, provide Entecavir and carrier material solid dispersion, and preparation method thereof, compositions is used and preparation;
Second aspect provides the solid dispersion of a kind of Entecavir and carrier material and other pharmaceutical carrier, and its preparation method, application.
The inventor finds: when in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil one or more exist, can improve dissolution and the dissolubility of Entecavir in water well, and within the specific limits, along with one or more the amount in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil increases, the dissolution of Entecavir and dissolubility also can further improve.Therefore, the present invention selects one or more carrier materials as the solid dispersion of Entecavir in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil for use.
At first, should be noted that following definition is applicable to whole description of the present invention and claims:
(1) " Entecavir " of the present invention comprising: Entecavir and solvate thereof, hydrate, various crystal formation, monocrystalline type, polymorphic, mixed crystal type, armorphous; The officinal salt that also comprises Entecavir, the biological effectiveness of finger reservation parent compound and characteristic, have with the pharmacological action of Entecavir equivalence, pharmaceutically acceptable medicinal acid addition salt, for example include but not limited to the hydrochlorate of Entecavir, mesylate, oxalates, acetate, lactate, gluconate, tartrate, citrate, fumarate, succinate, malate, maleate, benzoate, and the solvate of above-mentioned salt, hydrate, various crystal formations, monocrystalline type, polymorphic, mixed crystal type, armorphous Entecavir derivant salt material, or the like.Described above these all are the existence form of Entecavir as active ingredient.
(2) Polyethylene Glycol is the mixture that oxirane and water polycondensation form, and molecular formula is with HO (CH 2CH 2O) nH represents, wherein n represents the average of oxyethylene group, english abbreviation PEG, Polyethylene Glycol has various molecular weight and physical property, and under the normal temperature and pressure, molecular weight is that the Polyethylene Glycol of 100-700 is a liquid, molecular weight is that the Polyethylene Glycol more than 1000 is a solid, Polyethylene Glycol has very good hydrophilic, is a kind of pharmaceutic adjuvant commonly used on the pharmaceutics, safety non-toxic.Solid dispersion selectivity of the present invention uses normal temperature and pressure to be solid-state Polyethylene Glycol down, for example PEG1000, PEG1500, PEG2000, PEG3000, PEG4000, PEG5000, PEG6000, PEG7000, PEG8000, PEG9000, PEG10000, PEG15000, PEG20000 or the like, and above-mentioned any two or more mixture;
Polyoxyl stearate is a polyethylene glycol mono stearate, and molecular formula is with C 17H 35COO (CH 2CH 2O) nH represents that the normal temperature and pressure that the present invention selects for use for solid polyoxyl stearate class material, preferably uses polyoxyethylene stearate (40) ester, polyoxyethylene stearate (50) ester down, and n is about 40 or 50;
Sucrose fatty acid ester is called for short sucrose ester, it is the big compounds that sucrose and fatty acid response generate, belong to polyol-based non-ionic surfactant, according to different with the replacement number of fatty acid response generation ester, monoesters, diester, three esters and polyester are arranged, change substituted fatty acid and esterification degree, can obtain the sucrose fatty acid ester of different HLB values (5～18), sucrose fatty acid ester of the present invention comprise sucrose stearate, sucrose oleate, sucrose palmitate, Surfhope SE Cosme C 1216, Sucrose myristate etc. one or more;
Polyoxyethylene castor oil is made by Oleum Ricini and oxirane additive reaction, be nonionic surfactant, water soluble, ethanol etc. mainly contain polyoxyethylene (10) Oleum Ricini, polyoxyethylene (35) Oleum Ricini, polyoxyethylene castor oil, polyoxyethylene (60) Oleum Ricini, polyoxyethylene (100) Oleum Ricini, polyoxyethylene (150) Oleum Ricini, polyoxyethylene (200) Semen Ricini wet goods.
(3) " pharmaceutical composition " of the present invention is meant the semi-finished product that contain medicament active composition and pharmaceutic adjuvant composition, preparation, preparation compositions etc.
(4) " carrier material " of the present invention refers to form with Entecavir the basic material or the pharmaceutic adjuvant of solid dispersion, comprises in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil one or more.
(5) " pharmaceutical carrier " of the present invention is meant in pharmaceutical preparation (or in compositions), except that the principal agent composition, can be used for diluting, the pharmaceutic adjuvant or the excipient of filling, bonding, disintegrate, lubricated, painted, seasoning, moistening etc., pharmaceutical carrier also can form the disperse system of Entikawei solid dispersion or the solid dispersion of multicomponent system with " carrier material " described in (3).
(6) " solid dispersion " of the present invention is meant a kind of disperse system that exists with solid form that the medicine high degree of dispersion is formed in solid carrier (dispersion material), perhaps high degree of dispersion is in liquid-carrier and make the disperse system of solid preparation, the latter such as soft capsule.
First aspect contains Entecavir and carrier material
Solid dispersion, and preparation method thereof, medicinal application
The invention provides a kind of solid dispersion of Entecavir, contain Entecavir and carrier material, described carrier material is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more, wherein the quality ratio range of Entecavir and carrier material is 1: (1～150), the Polyethylene Glycol of the Entecavir of promptly per 1 gram and 1 to 150 gram, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more carry out proportioning and the solid dispersion that forms;
The quality ratio range of preferred Entecavir and carrier material is 1: (1～140);
The quality ratio range of preferred Entecavir and carrier material is 1: (2～130);
The quality ratio range of preferred Entecavir and carrier material is 1: (3～120);
The quality ratio range of preferred Entecavir and carrier material is 1: (4～110);
The quality ratio range of preferred Entecavir and carrier material is 1: (5～100);
The quality ratio range of preferred Entecavir and carrier material is 1: (6～90);
The quality ratio range of preferred Entecavir and carrier material is 1: (7～80);
The quality ratio range of preferred Entecavir and carrier material is 1: (8～70);
The quality ratio range of preferred Entecavir and carrier material is 1: (9～60);
The quality ratio range of preferred Entecavir and carrier material is 1: (10～50);
The quality ratio range of preferred Entecavir and carrier material is 1: (1～50);
The quality ratio range of preferred Entecavir and carrier material is 1: (2～40);
The quality ratio range of preferred Entecavir and carrier material is 1: (3～30);
The quality ratio range of preferred Entecavir and carrier material is 1: (4～20);
The quality ratio range of preferred Entecavir and carrier material is 1: (3～20).
For example, Entecavir and Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the quality proportioning of one or more in the polyoxyethylene castor oil is 1: 0.6,1: 0.8,1: 0.9,1: 1,1: 1.2,1: 1.3,1: 1.4,1: 1.5,1: 1.6,1: 1.7,1: 1.8,1: 1.9,1: 2,1: 2.2,1: 2.5,1: 2.8,1: 3,1: 3.5,1: 4,1: 4.5,1: 5,1: 5.5,1: 6,1: 6.5,1: 7,1: 7.5,1: 8,1: 8.5,1: 9,1: 9.5,1: 10,1: 11,1: 12,1: 13,1: 14,1: 15,1: 16,1: 17,1: 18,1: 19,1: 20,1: 25,1: 30,1: 35,1: 40,1: 45,1: 50,1: 55,1: 60,1: 65,1: 70,1: 75,1: 80,1: 90,1: 100,1: 110,1: 120,1: 130,1: 150, or the like.The present invention defines Entecavir and is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the quality ratio range of one or more in the polyoxyethylene castor oil, be based on the consideration of the composite factors such as medicinal application of improving Entecavir dissolution and deliquescent percentage contribution and solid dispersion, if Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the consumption of one or more in the polyoxyethylene castor oil is very few, and the dispersion of Entecavir in solid dispersion can not exclusively and improve its dissolution and dissolubility is not remarkable; If the consumption of one or more in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil is too much, the content of dispersion of Entecavir in dispersion is low and improve its dissolution and deliquescent percentage contribution is inconsiderable yet, also is unfavorable for application and the cost accounting of postorder when producing preparation compositions.
The present invention also provides five kinds of preparation methoies of the solid dispersion of Entecavir and carrier material (one or more in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil):
Method one. solvent method, this method comprises: get Entecavir and carrier material, add solvent, in 20 ℃ to the scope of solvent boiling point temperature, stirring is dissolved or dispersed in the solvent Entecavir and carrier material, from this mixture, remove behind the mix homogeneously and desolvate, and the dry solid dispersion that obtains with pulverizing, wherein said carrier material selects Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more, described solvent are selected from water (for example distilled water or purified water), dimethyl acetylamide, dimethyl formamide, methanol, ethanol, isopropyl alcohol, acetone, in the chloroform one or more.In above-mentioned preparation, remove and to desolvate and exsiccant method can be taked Rotary Evaporators to steam to remove, removes under reduced pressure, in the drying under reduced pressure, vacuum drying, lyophilization, spray drying, fluid bed drying, heating, drying one or more.
Method two. fusion method, this method comprises: get carrier material, add Entecavir in 50～90 ℃ after being heated to complete fusion, mix, after cooling is solidified it, pulverize, promptly obtain solid dispersion, wherein said chilling temperature is below 25 ℃, preferred below 10 ℃ (as 5 ℃, 0 ℃,-5 ℃,-10 ℃,-15 ℃,-18 ℃,-20 ℃,-25 ℃,-30 ℃ or the like), optionally can further solid dispersion drying under reduced pressure (comprising vacuum drying) be beneficial to pulverize and preserve, described carrier material is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more.
Method three. solvent-fusion method, this method comprises: get carrier material in 50～90 ℃ be heated to complete fusion after, add water, dimethyl acetylamide, dimethyl formamide, methanol, ethanol, isopropyl alcohol, the dissolved Entecavir solution of acetone or chloroform, mix, remove and desolvate, and the dry solid dispersion that obtains with pulverizing, wherein said carrier material is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more, in above-mentioned preparation, described remove desolvated and exsiccant method can be taked Rotary Evaporators to steam to remove, remove under reduced pressure, drying under reduced pressure, vacuum drying, lyophilization, spray drying, fluid bed drying, in the heating, drying one or more.
The amount of described liquid is Entecavir and carrier material total amount 3～15 times, described remove liquid and drying can adopt remove under reduced pressure, drying under reduced pressure, spray drying, lyophilization, fluid bed drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
Method four. polishing, this method comprises: Entecavir and carrier material are made pastel with suitable liquid, pastel is ground, further remove liquid and dry, pulverize, promptly get the solid dispersion of Entecavir and carrier material, wherein said carrier material is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more, described liquid is selected from water, dimethyl acetylamide, dimethyl formamide, methanol, ethanol, isopropyl alcohol, acetone, chloroform, in the dichloromethane one or more, described liquid and the drying of removing can adopt and remove under reduced pressure, drying under reduced pressure (comprising vacuum drying), spray drying, lyophilization, fluid bed drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry.Preferably, when the preparation pastel, the amount of liquid is Entecavir and carrier material total amount 3～15 times, for example 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times etc.
Method five. polishing, this method comprises: get carrier material and Entecavir, put in the mortar and grind, 100～600 rev/mins of rotating speeds, milling time 10～150min takes out, and crosses 80～200 mesh sieves, promptly get solid dispersion of the present invention, wherein said carrier material is selected from one or more in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil.
In above-mentioned preparation method four and the method five, the mode of described grinding can be carried out in such as grinder, extruder, homogenizer or blade blender.
The above-mentioned preparation method of the present invention all can be with Entecavir and described carrier material homodisperse, resulting solid dispersion, it is the pressed powder of high degree of dispersion, the Entecavir high degree of dispersion is in carrier material, under the Action of Surfactant of carrier material, and carrier material has changed the gathering or the crystalline form of Entecavir molecule, can make the dissolution and the dissolubility of Entecavir significantly improve, the solid dispersion of Entecavir and carrier material can be seen a kind of composition with pharmacologically active as, come useful in preparing drug formulations to seem very easy and be easy to guarantee the quality of pharmaceutical preparation with this solid dispersion, therefore, the solid dispersion that the present invention also provides Entecavir and carrier material contains application in the pharmaceutical preparation of Entecavir, the application in the hepatitis b virus infected medicine of preparation treatment in preparation.
Can pass through the administration Entecavir of the present invention of any appropriate and the solid dispersion of carrier material, but usually by oral or parenteral route.Use in order to carry out this class, the solid dispersion of Entecavir and carrier material can be prepared as acceptable any pharmaceutical dosage form on the pharmaceutics by adding suitable pharmaceutical carrier, and but, the definite form of said composition depends on form of medication naturally.
When the above-mentioned Entecavir and the solid dispersion of carrier material are used for the treatment of as active ingredient, can directly give the patient simple Entecavir and the solid dispersion of carrier material, for example with solid dispersion with the form of powder or directly the fill capsulae vacuus to give the patient oral, but sign in the assurance of the multiformity and the medicament quality of pharmaceutical dosage form, usually all be form appearance with the pharmaceutical composition that contains conventional pharmaceutically suitable carrier, therefore, the present invention also provides a kind of pharmaceutical composition, contain solid dispersion of the present invention and pharmaceutically suitable carrier, wherein in unit formulation, the content of the Entecavir that solid dispersion provided of Entecavir is 0.2mg～10mg;
The content of preferred Entecavir is 0.25mg～5mg;
The content of preferred Entecavir is 0.5mg～1mg.
Below for example 0.3mg, 0.5mg, 1mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5mg, or the like.Above-described compositions, " unit formulation " is meant the medicament of every one preparation compositions or individual packaging, for example each tablet (comprises dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets etc.), each hard capsule (comprises gastric solubleness, enteric, the slow release hard capsule), each soft capsule (comprises gastric solubleness, enteric soft capsules), per 1 to 1000 pill (comprises drop pill, micropill, because of its volume little, so a number of any integer word is decided to be a unit in will per 1 to 1000), each bag granule, each bag dry suspension, each bag powder, each bottleneck clothes liquid agent, each bottle (or bag) injection, each bottle powder ampoule agent for injection, or the like.
Should be understood that, on the one hand, in Entecavir of the present invention and carrier material of the present invention----Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil one or more, wherein said carrier material also can be regarded the pharmaceutical carrier of Entecavir as, be this carrier be not the simple pharmaceutical carrier that mixes with Entecavir on the meaning, but by the blend of unconventional technology with Entecavir and described carrier material formation high degree of dispersion; On the other hand, will be clear that, pharmaceutically suitable carrier of routine of the present invention is meant in pharmaceutical preparation (or in compositions), except that the principal agent composition, can be used for diluting, the pharmaceutic adjuvant or the excipient of filling, bonding, disintegrate, promotion dissolving or stripping, lubricated, painted, seasoning, moistening etc.
But be suitable for oral, non-intestinal or topical and can be tablet, hard capsule, soft capsule, pill, granule, dry suspension, powder, oral fluid agent, injectable or infusion solution or suspension, suppository, lozenge and transcutaneous device like this by being mixed with compositions and they.The Orally administered composition compositions of preferred oral administration, particularly molding or solid is because they are more convenient for generally using.
According to the difference of pharmaceutical dosage form, optionally can also optionally contain other suitable pharmaceutical carrier, such as diluent, filler, disintegrating agent, surfactant, suspending agent, binding agent, lubricant, coloring agent, flavoring agent etc.Described " optionally containing " is meant and can selects wherein one or more, also can not select.
There is and contains excipient commonly used in oral administration with unit dose usually with tablet (ordinary tablet, dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, special-shaped tablets etc.), capsule (hard capsule, soft capsule, enteric coated capsule etc.), granule, dry suspension, powder, pill (micropill, drop pill) and oral liquid (solution, suspension, emulsion agent), such as diluent, filler, disintegrating agent, surfactant, suspending agent, binding agent, lubricant, coloring agent, flavoring agent etc.
Used suitable filler or diluent comprise lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, or the like; Described disintegrating agent comprises sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, pregelatinized Starch, corn starch, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, or the like; Described surfactant comprises sodium lauryl sulphate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), or the like; Described suspending agent includes but not limited to hydroxypropyl emthylcellulose, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose, or the like; Described binding agent comprises polyvidone, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like; Described lubricant comprises magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate, or the like.In addition, also can comprise pH value regulator or buffer agent, for example phosphate buffer, citric acid, sodium citrate, acetate buffer, dilute hydrochloric acid, sodium carbonate, sodium hydroxide, or the like; Also can comprise antiseptic, for example sodium benzoate, potassium sorbate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, or the like; Also can comprise stabilizing agent and antioxidant, for example calcium disodium edetate, sodium sulfite, vitamin C, vitamin E, or the like; Also can comprise the taste regulator, for example maltose alcohol, steviosin, aspartame, fructose, sucrose, saccharin sodium, flavoring orange essence, strawberry essence, or the like; Also can comprise additive other routine, appropriate in addition.
Further, the present invention also provides the preparation of drug combination method of the solid dispersion that contains Entecavir and carrier material, this method comprises the solid dispersion of Entecavir and pharmaceutically acceptable, suitable pharmaceutical carrier fully is mixed and made into acceptable any pharmaceutical dosage form on the pharmaceutics, and preferred pharmaceutical dosage form is that tablet (comprises dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, special-shaped tablets etc.), hard capsule (comprises gastric solubleness, enteric, slow releasing capsule), soft capsule (comprises gastric solubleness, enteric soft capsules), drop pill, pellet, granule, dry suspension, powder, oral fluid agent (comprises solution, suspension, emulsion agent), injection (comprising powder ampoule agent for injection and injection) etc.Can mix by solid dispersion and pharmaceutically suitable carrier/fusion/fusion/dissolution Entecavir, common method such as granulation, filling, tabletting/fill gelatine capsule, compacting/drip system soft capsule prepares solid oral composition.Can use the operation of fusion repeatedly to be distributed in the pharmaceutical carrier so that make the abundant mixing of active ingredient; When preparation hard gelatin capsule and tablet, can adopt fill gelatine capsule or tabletting after the wet granulation drying, also can adopt fill gelatine capsule or tabletting behind the dry granulation, also can be with direct fill gelatine capsule of the solid dispersion of Entecavir and carrier material or tabletting; When the preparation soft capsule, the Polyethylene Glycol that the solid dispersion dissolving or the dispersion of Entecavir and carrier material can be liquid state at normal temperatures is (as PEG300, PEG400, PEG600 etc.) or after forming liquid or soft plastic state mixture in the vegetable oil (as soybean oil, the corn wet goods) obtain soft capsule with the soft capsule material of gelatin environmental sealing; When preparation during drop pill, can with room temperature down for solid-state Polyethylene Glycol (as PEG3000, PEG4000, PEG6000, PEG8000 etc.) behind the heating and melting, make solid dispersion dissolving or be dispersed in the Polyethylene Glycol, form behind the liquefied mixture with drip the system machine system of dripping and cool off after obtain drop pill; Perhaps will after dripping system machine system of dripping and cooling, obtain drop pill behind the solid dispersion heating and melting of Entecavir and glyceryl monostearate, polyoxyl stearate.Certainly, in the above-mentioned preparation, optionally also can add other pharmaceutic adjuvant, as disintegrating agent, surfactant, lubricant etc.
It is also understood that when pharmaceutical dosage form is tablet or capsule, can be the film coating.Can give tablet coating (enteric coating or gastric solubleness film-coat) according to method well-known in the art, the material that is used for the film coating, comprise suitable coating materials, for example Opadry, hydroxypropyl methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, or the like; Also can comprise plasticizer, for example Polyethylene Glycol, triethyl citrate, or the like.The coating membrane color can be various, as orange colour, white, blueness or the like.
Preferred pharmaceutical dosage form is tablet (comprising dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, special-shaped tablets etc.), hard capsule (comprising gastric solubleness, enteric, slow releasing capsule), soft capsule (comprising gastric solubleness, enteric soft capsules), drop pill, pellet, granule, powder, oral fluid agent (comprising solution, suspension, emulsion agent), injection (comprising powder ampoule agent for injection and injection) etc.
Particularly, by adopting wet granulation or dry granulation to obtain granule or dry suspension behind the solid dispersion of Entecavir of the present invention and the pharmaceutical carrier mix homogeneously, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
By obtaining dry suspension or powder behind the solid dispersion of Entecavir and the pharmaceutical carrier mix homogeneously, optionally can further dry suspension or powder fill Capsules shell be obtained hard capsule, perhaps mix homogeneously obtains granule behind wet granulation or the dry granulation, to obtain hard capsule in the granule fill Capsules shell, wherein the solid medicinal carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
By obtaining soft capsule with dripping to make to seal with soft capsule material compacting of gelatin or capsule material glue behind the solid dispersion of Entecavir and the suitable pharmaceutical carrier mix homogeneously, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: Liquid Macrogol, PEG400, Macrogol 600, soybean oil, Semen Maydis oil, other vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described " soft capsule material compacting or the capsule material glue system of dripping are sealed " is meant and adopts pressing or dropping preparation method to prepare soft capsule, pressing is meant that the liquid or soft plastic state content that adopts press will contain solid dispersion wraps up formation preparation of soft capsule method with the compacting of capsule material film, can be pressed into different shapes and content content with different moulds, usually seal the capsule preparation with rotating the continuously automatic soft capsule production machine of rolling capsule machine or punching type automatically, dropping preparation method is meant the method that is equipped with soft capsule by a making mechanism, at a certain temperature, generally remain on more than 45 ℃, it is biphase utilizing capsule material glue and liquid content, after making a certain amount of capsule material glue with quantitative liquid content parcel, splash into that (condensed fluid can be a liquid paraffin in the another kind of not miscible condensed fluid, methyl-silicone oil, vegetable oil, in the kerosene any one), behind the capsule material glue condensation by contact liquid, owing to surface tension effects makes it to solidify the spherical soft capsule of formation; Or
Because Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate also can be as the good substrate of preparation drop pill, by with Entecavir and Polyethylene Glycol, glyceryl monostearate, after the solid dispersion melting mixing of polyoxyl stearate is even, or with Entecavir and Polyethylene Glycol, glyceryl monostearate, after the mixture melting mixing of polyoxyl stearate is even, splash in the not miscible condensed fluid, shrink condensation and make drop pill, optionally drop pill can contain but be not limited to following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, can contain but be not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with the solid dispersion of Entecavir and suitable pharmaceutical carrier melting mixing evenly after, splash in the not miscible condensed fluid, shrink condensation and make drop pill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: cetomacrogol 1000, polyethylene glycol 1500, Macrogol 3000, Macrogol 4000, Polyethylene Glycol 5000, polyethylene glycol 6000, Polyethylene Glycol 7000, Polyethylene Glycol 8000, Polyethylene Glycol 9000, cetomacrogol 1000 0, stearic acid, sodium stearate, hydrogenated vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with behind the solid dispersion of Entecavir and the suitable pharmaceutical carrier mix homogeneously, make the solid preparation of spherical or near-spherical, perhaps with the solid dispersion of Entecavir and suitable pharmaceutical carrier dissolving or molten being dispersed in the liquid medium, and its deposition is coated on the surface of celphere and forms micropill, wherein the solid medicinal carrier includes but not limited to the following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth) obtains the drop pill capsule in the capsulae vacuus of optionally can further micropill being packed into; Or
By the solid dispersion of Entecavir and water or aqueous liquid mixing are evenly formed oral administration solution or suspension; Or
By solid dispersion and suitable injection pharmaceutical carrier mix homogeneously with Entecavir, can obtain injection by the injection preparation method, wherein pharmaceutical carrier includes but not limited to the following material as filler or excipient: water, mannitol, sorbitol, lactose, xylitol, fructose, dextran, glucose, sodium chloride.
Optionally, difference and the needs of guaranteeing the medicament quality according to pharmaceutical dosage form can also add other suitable pharmaceutic adjuvant in the above-mentioned preparation method.
Second aspect contains Entecavir, carrier material and other is medicinal
Carrier solid dispersion, and preparation method thereof, medicinal application
On the other hand, the present invention also provides the solid dispersions technique of a kind of Entecavir and described carrier material and other pharmaceutical carrier, wherein contain Entecavir, carrier material and other pharmaceutical carrier, the quality ratio range of Entecavir and carrier material is 1: (1～150), be that carrier material that the Entecavir and 1 to 150 of per 1 gram restrains carries out proportioning and the solid dispersion that forms, described carrier material is selected from one or more in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil;
The quality ratio range of preferred Entecavir and carrier material is 1: (1～140);
The quality ratio range of preferred Entecavir and carrier material is 1: (2～130);
The quality ratio range of preferred Entecavir and carrier material is 1: (3～120);
The quality ratio range of preferred Entecavir and carrier material is 1: (4～110);
The quality ratio range of preferred Entecavir and carrier material is 1: (5～100);
The quality ratio range of preferred Entecavir and carrier material is 1: (6～90);
The quality ratio range of preferred Entecavir and carrier material is 1: (7～80);
The quality ratio range of preferred Entecavir and carrier material is 1: (8～70);
The quality ratio range of preferred Entecavir and carrier material is 1: (9～60);
The quality ratio range of preferred Entecavir and carrier material is 1: (10～50);
The quality ratio range of preferred Entecavir and carrier material is 1: (1～50);
The quality ratio range of preferred Entecavir and carrier material is 1: (2～40);
The quality ratio range of preferred Entecavir and carrier material is 1: (3～30);
The quality ratio range of preferred Entecavir and carrier material is 1: (4～20);
The quality ratio range of preferred Entecavir and carrier material is 1: (3～20).
For example, Entecavir and Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the quality proportioning of one or more in the polyoxyethylene castor oil is 1: 1,1: 1.2,1: 1.3,1: 1.4,1: 1.5,1: 1.6,1: 1.7,1: 1.8,1: 1.9,1: 2,1: 2.2,1: 2.5,1: 2.8,1: 3,1: 3.5,1: 4,1: 4.5,1: 5,1: 5.5,1: 6,1: 6.5,1: 7,1: 7.5,1: 8,1: 8.5,1: 9,1: 9.5,1: 10,1: 11,1: 12,1: 13,1: 14,1: 15,1: 16,1: 17,1: 18,1: 19,1: 20,1: 25,1: 30,1: 35,1: 40,1: 45,1: 50,1: 55,1: 60,1: 65,1: 70,1: 75,1: 80,1: 90,1: 100,1: 110,1: 120,1: 130,1: 150, or the like.
Described other pharmaceutical carrier is such as diluent, filler, disintegrating agent, surfactant, suspending agent, binding agent, lubricant, coloring agent, flavoring agent etc.
According to the difference of pharmaceutical dosage form, optionally can optionally contain other suitable pharmaceutical carrier, such as diluent, filler, disintegrating agent, surfactant, suspending agent, binding agent, lubricant, coloring agent, flavoring agent etc.Described " optionally containing " is meant and can selects wherein one or more, also can not select.
Described suitable filler or diluent include but not limited to lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, or the like; Described disintegrating agent includes but not limited to sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, pregelatinized Starch, corn starch, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, or the like; Described surfactant comprises but is not limited to sodium lauryl sulphate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), or the like; Described suspending agent includes but not limited to hydroxypropyl emthylcellulose, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose, or the like; Described binding agent includes but not limited to methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like; Described lubricant includes but not limited to magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate, or the like.In addition, can also comprise pH value regulator or buffer agent, for example phosphate buffer, citric acid, sodium citrate, acetate buffer, dilute hydrochloric acid, sodium carbonate, sodium hydroxide, or the like; Also can comprise antiseptic, for example sodium benzoate, potassium sorbate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, or the like; Also can comprise stabilizing agent and antioxidant, such as but not limited to calcium disodium edetate, sodium sulfite, vitamin C, vitamin E, or the like; Also can comprise the taste regulator, for example maltose alcohol, steviosin, aspartame, fructose, sucrose, saccharin sodium, flavoring orange essence, strawberry essence, or the like.
Technical solution of the present invention has come down to provide with carrier material and other suitable pharmaceutical carrier and has formed binary vector or polynary carrier, forms the solid dispersion system of disperseing Entecavir to reach.
Certainly,, optionally can also use additive other routine, appropriate or pharmaceutic adjuvant,, can be selected from water, ethanol, water-ethanol solution etc. as wetting agent according to the difference of pharmaceutical dosage form.
Further, the present invention also provides the above-mentioned Entecavir that contains, the preparation method of the solid dispersion of carrier material of the present invention and other pharmaceutical carrier, it comprises Entecavir, carrier material of the present invention and other pharmaceutical carrier fully are mixed and made into any pharmaceutical dosage form of acceptable on the pharmaceutics, and preferred pharmaceutical dosage form is that tablet (comprises dispersible tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, special-shaped tablets etc.), hard capsule (comprises gastric solubleness, enteric, slow releasing capsule), soft capsule (comprises gastric solubleness, enteric soft capsules), drop pill, pellet, granule, dry suspension, powder, oral fluid agent (comprises solution, suspension, emulsion agent), injection (comprising powder ampoule agent for injection and injection) etc.
Pharmaceutical dosage form is relevant with the preparation method of selected pharmaceutical carrier and postorder.
Particularly, by with Entecavir, carrier material is dissolved or dispersed in alcohol, in the alcohol-water solution, with this liquid mixture as wetting agent to the pharmaceutical carrier wet granulation, remove and desolvate and drying, make the granule or the dry suspension of dispersion, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein other pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose, described alcohol, alcohol-water solution comprises ethanol, methanol, ethanol-water solution, methanol-water solution, described remove desolvated and drying can adopt and removes under reduced pressure, drying under reduced pressure (comprising vacuum drying), spray drying, lyophilization, fluid bed drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
By with Entecavir, carrier material and other pharmaceutical carrier are dissolved or dispersed in alcohol, in the alcohol-water solution, stir or fully grind the back and remove and desolvate and dry, with solid drying and the pulverizing that obtains, promptly obtain the dry suspension or the powder of dispersion, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein other pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose, described alcohol, alcohol-water solution comprises ethanol, methanol, ethanol-water solution, methanol-water solution, wherein said remove desolvated and drying can adopt and removes under reduced pressure, drying under reduced pressure (comprising vacuum drying), spray drying, lyophilization, fluid bed drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
By with Entecavir, carrier material and other pharmaceutical carrier are dissolved or dispersed in the liquid Polyethylene Glycol or vegetable oil, seal or the capsule material glue system of dripping is sealed and obtained soft capsule with the compacting of the soft capsule material of gelatin, other pharmaceutical carrier includes but not limited to the following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), wherein Polyethylene Glycol includes but not limited to Liquid Macrogol, PEG400, Macrogol 600, vegetable oil includes but not limited to soybean oil, Semen Maydis oil; Or
By with Entecavir, after carrier material and other pharmaceutical carrier melting mixing are even, splash in the not miscible condensed fluid, shrink condensation and make drop pill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: cetomacrogol 1000, polyethylene glycol 1500, Macrogol 3000, Macrogol 4000, Polyethylene Glycol 5000, polyethylene glycol 6000, Polyethylene Glycol 7000, Polyethylene Glycol 8000, Polyethylene Glycol 9000, cetomacrogol 1000 0, polyoxyethylene stearate (40) ester, glyceryl monostearate, stearic acid, sodium stearate, hydrogenated vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or,
By with Entecavir, behind carrier material and other pharmaceutical carrier mix homogeneously, be dissolved or dispersed in alcohol, in the alcohol-water solution, make the solid preparation of spherical or near-spherical and make micropill, perhaps with Entecavir, carrier material is with other pharmaceutical carrier dissolving or be dispersed in alcohol, in the alcohol-water solution medium, and its deposition is coated on the surface of celphere and makes micropill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth) obtains pellet capsule in the capsulae vacuus of optionally can further micropill being packed into.
Above-mentioned preparation contains in the preparation method of solid dispersion of Entecavir, carrier material and other pharmaceutical carrier, described " carrier material " comprises and is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil one or more, and described " being scattered in alcohol, alcohol-water solution " is meant that material forms with homodisperse states such as suspension, suspension, emulsion, colloids in liquid medium.Should be appreciated that substance dissolves is the dispersity of topnotch in liquid medium, and dispersive states such as the suspension that forms, suspension, emulsion, colloid also are good dispersities in liquid is situated between.The inventor is by repeatedly experiment discovery, less and not simultaneously when the consumption of liquid medium, material is easy to form dispersion states such as suspension, suspension, emulsion, colloid, and the prepared solid dispersion that contains Entecavir, carrier material and other pharmaceutical carrier accordingly and the difference of formulations prepared from solutions are little.
Optionally, can also add other suitable pharmaceutic adjuvant in the above-mentioned preparation method.
Though the invention describes Entecavir be selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil one or more solid dispersion and the concrete related content of two aspects such as their preparation and medicinal application, also should be included within the scope of the invention conspicuous some modification of experienced technical staff in the art or the situation that is equal to.
Also should be noted that; the invention provides Entecavir and Polyethylene Glycol; glyceryl monostearate; polyoxyl stearate; sucrose fatty acid ester; the technology contents of two aspects of the solid dispersion of one or more in the polyoxyethylene castor oil; and define Entecavir and Polyethylene Glycol pointedly; glyceryl monostearate; polyoxyl stearate; sucrose fatty acid ester; the dose-effect scope of one or more in the polyoxyethylene castor oil; Polyethylene Glycol; glyceryl monostearate; polyoxyl stearate; sucrose fatty acid ester; in the polyoxyethylene castor oil one or more can be regarded the dispersant and the chaotropic agent of Entecavir as in solid dispersion (or preparation compositions); solubilizing agent; but Polyethylene Glycol no matter; glyceryl monostearate; polyoxyl stearate; sucrose fatty acid ester; being with which kind of purpose and bearing which kind of task of in the polyoxyethylene castor oil one or more; as long as existing within the dose-effect scope that solid dispersion of the present invention limits of it all should be included within protection scope of the present invention.
Solid dispersion of the present invention is at tablet especially dispersible tablet, can reach good preparation effect in the application of quickly disintegrating tablet and the preparation, need to prove, in the preparation of tablet, especially in the preparation of dispersible tablet, the selection of disintegrating agent and use are very important, the key of dispersible tablet is its disintegration rate in water, so the selection of the disintegrating agent system in the tablet is extremely important, dispersible tablet provided by the present invention, at least a carboxymethyl starch sodium (CMS-Na) that is selected from of the disintegrating agent of choosing, low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl cellulose (CMC-Na), crospolyvinylpyrrolidone (PVPP), cross-linking sodium carboxymethyl cellulose (cCMC-Na), crosslinked carboxymethyl fecula sodium (cCMS-Na), microcrystalline Cellulose (MCC), carboxymethylcellulose calcium (CMC-Ca); In preparation process, disintegrating agent is made granule with the prescription powder, is referred to as addition in the disintegrating agent; Disintegrating agent mixes the back tabletting and is referred to as the outer addition of disintegrating agent with dried granules.Add in the disintegrating agent and add the speed that all can influence the dispersible tablet disintegrate, can adopt interior addition, also can adopt outer addition, can also in add, add common use; interiorly add, when adding common use, disintegrating agent can be identical, also can be different.This kind tablet, easy disintegrating disperses, and helps the stripping and the diffusion of Entecavir.
Also need to prove, in the preparation of micropill, celphere is meant the prefabricated profiled microspheroidal ball that does not contain the medicine active ingredient, it is a kind of intermediate pharmaceutic adjuvant, usually outward appearance is spherical shape, the adjuvant that is used for celphere mainly contains filler and binding agent, optionally also can add a certain amount of disintegrating agent, porogen, lubricant and surfactant etc., can not only improve its dissolving, disintegrate, the outward appearance rounding property, also can improve its further machinability, as coating, be easy to performances such as drying, celphere can be buied from the market with the product of pharmaceutic adjuvant, as sucrose-starch celphere (35 to 40 order), microcrystalline Cellulose celphere, sucrose celphere.Pellet or drop pill, specific surface area is big, easily disperses and contacts with water, helps the stripping and the diffusion of Entecavir.Same, granule provided by the invention, dry suspension, powder because the medicine high degree of dispersion is easy to contact with water, help the stripping and the diffusion of Entecavir.Soft capsule because content is liquid or soft plastic state, has been the pre-wetted state, be easier to aqueous dispersion with contact with water, stripping.
Pharmaceutical dosage form of the present invention, (comprise dispersible tablet as tablet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, special-shaped tablets etc.), hard capsule (comprises gastric solubleness, enteric, slow releasing capsule), soft capsule (comprises gastric solubleness, enteric soft capsules), pellet, granule (comprises effervescent granule, enteric coated particles etc.), dry suspension, powder, oral fluid agent (comprises solution, suspension, emulsion agent), injection (comprising powder ampoule agent for injection and injection) etc., more than these pharmaceutical dosage forms " all on the books and describe in the Chinese pharmacopoeia at 2005 editions.
The implication of nouns such as diluent of the present invention, filler, disintegrating agent, surfactant, suspending agent, binding agent, lubricant, coloring agent, flavoring agent belongs to the pharmaceutics category, be that those skilled in the art are familiar with maybe should being familiar with, should be able to understand the intention of the inventor for these nouns.For example: flavoring agent can be understood that to cover the pharmaceutic adjuvant (or additive) of bitter taste of drug or improvement taste perception very easily, purposes such as accent is sweet such as reaching, acid adjustment, perfumery, good mouthfeel can allow the patient be easy to accept pharmaceutical preparation, as effervescent tablet, oral cavity disintegration tablet, chewable tablet, granule, dry suspension, powder, oral fluid agent.
In addition, " including but not limited to " of the present invention is meant and comprises in the concrete material that is outlined one or more, but also can be outline outside, those skilled in the art can predict and to obtain, play the material of effect same and effect, for example " vegetable oil includes but not limited to soybean oil; Semen Maydis oil " refers to comprise soybean oil and/or Semen Maydis oil, but also comprise in addition vegetable oil or the oils and fats of its extraction, as Oleum Arachidis hypogaeae semen, olive oil, Fructus Maydis oil, soybean salad oil, rape salad oil, the corn salad oil, Petiolus Trachycarpi oil, olive oil, Oleum Gossypii semen, Oleum sesami, Oleum Helianthi, chilli oil, Oleum Ricini, Oleum Brassicae campestris, oleic acid, ethyl oleate, hydrogenated vegetable oil, lecithin, fabaceous lecithin, plant embryo oil, Oleum Camelliae or the like.
Entecavir provided by the invention and one or more the solid dispersion that is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil, be off-white color or yellow-white powder, mobile good, stable in properties.Adopt differential scanning calorimetric analysis (DSC), X-ray diffraction analysis that the solid dispersion of prepared different quality proportioning is investigated.DSC result shows that the DSC absworption peak of Entecavir concentrates on 238～241 ℃, and does not observe the fusing point peak of Entecavir in the solid dispersion or do not have tangible fusing point peak; X-ray diffraction analysis is the result show, in the solid dispersion of Entecavir and described carrier material, Entecavir mainly is scattered in wherein with microcrystalline form or unformed state, has formed coprecipitate or eutectic mixture.
The solid dispersion of one or more in Entecavir of the present invention and Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil is used to prepare the hepatitis b virus infected pharmaceutical composition of treatment.Further, the solid dispersion of one or more in Entecavir of the present invention and Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil and preparation thereof, the application in the hepatitis b virus infected medicine of preparation treatment.
In addition, the solid dispersion of Entecavir provided by the invention can be used as the principal agent composition, with other appropriate drug active ingredient, makes compound preparation; Perhaps Entecavir and other appropriate drug active ingredient are made solid dispersion with carrier material of the present invention, good pharmacology synergism is arranged to reach with Entecavir.
Verify further that with following test one or more solid dispersion in Entecavir of the present invention and Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil is at the significant advantage of aspects such as the dissolubility of improving Entecavir and dissolution.
One. water-soluble is relatively
Under the normal temperature and pressure, record the dissolubility of Entecavir in water less than 2.5mg/ml;
The dissolubility of the solid dispersion of the solid dispersion of one or more in the Entecavir of each ratio of the present invention and Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil (in Entecavir) is all greater than 7mg/ml;
As seen, the solid dispersion of Entecavir of the present invention has very significant effect to the dissolubility raising of Entecavir.
Two. the dissolution test is relatively
The water solublity of the solid dispersion excellence of one or more in Entecavir and Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil has good facilitation for its stripping in preparation, especially for oral formulations, significant.
Be to be understood that oral medicament need absorb through gastrointestinal and just can enter blood of human body reaching antiviral effect, the quality of oral absorption directly affects the therapeutic effect of medicine.According to the notion of pharmaceutics, bioavailability (Bioavailability) refers to that medicine is absorbed to enter and sanguimotorly utilizes degree and utilize speed.Compare Entecavir, solid dispersion of the present invention has excellent water-soluble, enters aspect sanguimotor degree and the speed in absorption for the oral drug preparation that with it is active ingredient, has important facilitation and meaning.Medicament enters the absorption process behind the gastrointestinal, divide two stages, be that disintegrate dispersion and gastrointestinal wall absorb two stages, at first need in gastric juice or intestinal juice, disintegrate scatter, and then contact and be attached to gastrointestinal wall and absorb and enter blood, this two stages all can influence the performance with drug effect of absorbing of medicine, Entecavir is prepared as the good solid dispersion form of water solublity, the medicine dissolution rate is significantly accelerated, improved its dispersive degree of disintegrate and rate of dispersion in gastric juice or intestinal juice greatly, then medicament active composition is more abundant with contacting of gastrointestinal wall, be attached to that gastrointestinal wall absorbs and to enter the active ingredient of blood also more abundant, this raising for the bioavailability of efficacy component Entecavir is significant.
With following experiment the advantage of solid dispersion of the present invention stripping in preparation is described, the test of preparation dissolution is as follows.
Experimental technique: the selection of preparation model, lactose and pregelatinized Starch are the most frequently used pharmaceutic adjuvants in the oral formulations, are pharmaceutical excipient with lactose (50%) and pregelatinized Starch (49%) therefore, and magnesium stearate is lubricant (1%), respectively containing the Entecavir of 0.5mg, with:
Entecavir;
The solid dispersion of Entecavir and Polyethylene Glycol, Entecavir and glyceryl monostearate, Entecavir and polyoxyl stearate, Entecavir and sucrose fatty acid ester, Entecavir and polyoxyethylene castor oil (1: 4);
The solid dispersion of Entecavir and Polyethylene Glycol, Entecavir and glyceryl monostearate, Entecavir and polyoxyl stearate, Entecavir and sucrose fatty acid ester, Entecavir and polyoxyethylene castor oil (1: 9) is as active ingredient.
Sample preparation: with 30% ethanol water is the wet granulation that wetting agent is equal to, granulate, dry, tabletting, obtain Entecavir respectively, Entecavir and Polyethylene Glycol, Entecavir and glyceryl monostearate, Entecavir and polyoxyl stearate, Entecavir and sucrose fatty acid ester, the solid dispersion of Entecavir and polyoxyethylene castor oil (1: 4), Entecavir and Polyethylene Glycol, Entecavir and glyceryl monostearate, Entecavir and polyoxyl stearate, Entecavir and sucrose fatty acid ester, the solid dispersion of Entecavir and polyoxyethylene castor oil (1: 9) is that study model is tested the wherein stripping situation of active substance with this series.
Dissolution content assaying method: get the study model tablet, according to dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005 three therapeutic methods of traditional Chinese medicine), 250ml is a dissolution medium with phosphate buffer (pH6.8), rotating speed is that per minute 75 changes, operation in accordance with the law, in the time of 25 minutes, get solution 10ml and filter, get subsequent filtrate as need testing solution; Other gets the about 20mg of Entecavir reference substance, and accurate the title decides, and puts to add methanol 10ml, ultrasonic dissolution in the 100ml measuring bottle, add the stripping medium again to scale, shake up, precision is measured 1ml, put and add the stripping medium in the 100ml measuring bottle, shake up, in contrast product solution to scale.According to the chromatographic condition under the assay item, precision is measured each 20 μ l of above-mentioned two kinds of solution and is injected chromatograph of liquid, and the record chromatogram is by the stripping quantity of external standard method calculating tablet.Measure with the HPLC method, detect wavelength 255nm.Limit is 85% of a labelled amount, should be up to specification.
Measurement result shows:
The dissolution of tablet in the time of 25 minutes of the solid dispersion (1: 9) of the solid dispersion of Entecavir (1: 4), Entecavir is good, and its dissolution all significantly is better than the dissolution of (P＜0.05) Entecavir model sample, demonstrates solid dispersion good performance aspect the preparation stripping of Entecavir of the present invention.
In addition, because the content of Entecavir in the preparation of clinical practice is very low, in the formulation preparation process, be difficult to its mix homogeneously, and the present invention makes solid dispersion with Entecavir, it is other to have increased the thing magnitude that contains Entecavir, help the preparation in the postorder preparation production process, this also is one of advantage of Entikawei solid dispersion of the present invention.
The specific embodiment in implementation process of the present invention, various embodiments that those skilled in the art produce on the basis that does not depart from the scope of the present invention with spirit and modify conspicuous and be to carry out easily.Come the present invention done further specifying by the following examples, but do not represent the embodiment limitation of the present invention.
The solid dispersion (1: 4) of embodiment 1. Entecavirs and Macrogol 4000 and preparation
Getting 1g Entecavir and 4g Macrogol 4000 is dissolved in the ethanol of 172ml, steam except that (vacuum pump decompression) ethanol in Rotary Evaporators, to obtain solids scrapes and gets 32 ℃ of dry 24h in the rearmounted vacuum desiccator, pulverize 80 mesh sieves, promptly got the solid dispersion (1: 4) of Entecavir and Macrogol 4000.The accumulative total dissolution is 92.43% during its 10min.
The solid dispersion and the preparation of embodiment 2. Entecavirs and polyethylene glycol 6000
Similarly, press the preparation method of embodiment 1, the mass ratio that dissolves Entecavir and polyethylene glycol 6000 in an amount of distilled water respectively is 1: 1,1: 2,1: 3,1: 5,1: 6,1: 7,1: 8,1: 10,1: 20,1: 50,1: 80,1: 100,1: 130 a solids, reclaim distilled water in Rotary Evaporators (vacuum pump decompression) evaporation, collect solids, put and be dried to constant weight in the vacuum desiccator, pulverize 80 mesh sieves, promptly got the Entecavir of various different proportionings and the solid dispersion of polyethylene glycol 6000.
The solid dispersion (1: 25) of embodiment 3. Entecavirs and Polyethylene Glycol and preparation
Get 10gPEG8000 and 15g PEG3000 mixture, after heating in water bath to 68 ℃ makes its whole fusions and whisks mix homogeneously, add the 1g Entecavir, fully stir and make mix homogeneously, be cooled to 5 ℃ and make its curing, pulverize 60 mesh sieves, promptly got the solid dispersion (1: 25) of Entecavir and Polyethylene Glycol (mixture of PEG8000 and PEG3000).The accumulative total dissolution is 96.22% during its 10min.
The solid dispersion (1: 7) of embodiment 4. Entecavirs and glyceryl monostearate and preparation
Method one: get 61～63 ℃ of 7g glyceryl monostearate heating in water bath and make it be fused liquid state, add the 1g Entecavir, make mix homogeneously in 60～62 ℃ of abundant stirrings, place 0 ℃ to make curing, pulverize, and put 35 ℃ of dry 24h in the vacuum desiccator, and pulverized 80 mesh sieves, promptly get the solid dispersion (1: 7) of Entecavir and glyceryl monostearate.The accumulative total dissolution is 90.06% during its 10min.
Method two: after getting 7g glyceryl monostearate heating in water bath to 62 and ℃ it being in a liquid state, it is added the solution of 1g Entecavir in 110ml methanol, mixture is removed methanol in 55 ℃ of spray dryinges, the gained solids was pulverized 80 mesh sieves, promptly got the solid dispersion (1: 7) of Entecavir and glyceryl monostearate.The accumulative total dissolution is 90.65% during its 10min.
Method three: get the 7g glyceryl monostearate and 1 gram Entecavir adds the 280ml deionized water, place Rotary Evaporators to be spin-dried for water in 35 ℃, the gained solids was pulverized 80 mesh sieves, promptly got the solid dispersion (1: 7) of Entecavir and glyceryl monostearate.The accumulative total dissolution is 90.52% during its 10min.
Method four: get 1g Entecavir and 7g glyceryl monostearate, put in the mortar, add 24ml acetone, make pastel, grind 30min, fluid bed drying is removed acetone, with gained solids crushing screening, promptly get the solid dispersion (1: 7) of Entecavir and glyceryl monostearate.
Can make the solid dispersion of 1: 10,1: 12,1: 15,1: 40,1: 50,1: 60,1: 120 equal proportion with above-mentioned similar approach.
The solid dispersion (1: 4) of embodiment 5. Entecavirs and polyoxyl stearate and preparation
Get the 1g Entecavir and 4g polyoxyl stearate ester is dissolved in the 220ml ethanol, after stirring, decompression recycling ethanol, gained solids are put 35 ℃ of dry 12h in the vacuum desiccator, pulverize 80 mesh sieves, promptly got the solid dispersion (1: 4) of Entecavir and polyoxyl stearate.The accumulative total dissolution is 88.76.% during its 10min.
The solid dispersion (1: 24) of embodiment 6. Entecavirs and polyoxyl stearate and preparation
Getting 24g polyoxyethylene stearate (40) ester heating in water bath makes it be fused liquid state for 51～53 ℃, add the 1g Entecavir, fully stir and make mix homogeneously, place 5 ℃ to make curing, pulverize, and put 30 ℃ of dry 24h in the vacuum desiccator, and pulverized 80 mesh sieves, promptly get the solid dispersion (1: 24) of Entecavir and polyoxyl stearate.The accumulative total dissolution is 93.52% during its 10min.
Embodiment 7.
Similarly, press the method for the foregoing description 5,6, the mass ratio that can make Entecavir and polyoxyl stearate is 1: 1,1: 3,1: 5,1: 6,1: 10,1: 25,1: 35,1: 100,1: 165 a solid dispersion, off-white color or white yellow powder solid.(annotate: make the polyoxyl stearate heating be fused solution in 50～53 ℃, the 1g polyoxyl stearate can dissolve in the methanol of about 20ml or ethanol.)
The solid dispersion (1: 3) of embodiment 8. Entecavirs and sucrose fatty acid ester and preparation
Method one: get 5g Entecavir and 15g sucrose fatty acid ester (HLB=15) put in the mortar mix after, add 95ml acetone and make pastel, pastel is ground 1h, put vacuum drying oven and be dried to constant weight for 40 ℃, pulverize 80 mesh sieves, promptly got the solid dispersion (1: 3) of Entecavir and sucrose fatty acid ester.The accumulative total dissolution is 82.73% during its 10min.
Method two: get the 1g Entecavir and 3g sucrose fatty acid ester (HLB=17) is dissolved in the 200ml dimethyl acetylamide, stir in the rearmounted concentrating under reduced pressure instrument of 5min and reclaim dimethyl acetylamide, collect solids, 40 ℃ of vacuum drying 10h, pulverize 80 orders, promptly got the solid dispersion (1: 3) of Entecavir and sucrose fatty acid ester.The accumulative total dissolution is 83.31% during its 10min.
Can make the solid dispersion of 1: 1,1: 2.2,1: 4,1: 5,1: 6,1: 7 equal proportion with above-mentioned similar approach.
The solid dispersion (1: 5) of embodiment 9. Entecavirs and polyoxyethylene castor oil and preparation
Get 1g Entecavir and 5g polyoxyethylene castor oil put in the mortar mix after, add 58ml deionized water and alcoholic acid mixed solution (V: V=1: 1) make pastel, pastel is ground 1h, put vacuum drying oven and be dried to constant weight for 40 ℃, pulverize 80 mesh sieves, promptly got the solid dispersion (1: 5) of Entecavir and polyoxyethylene castor oil.The accumulative total dissolution is 93.75% during its 10min.
Embodiment 10.
Can make the solid dispersion of 1: 1,1: 2,1: 3,1: 3.5,1: 4.5,1: 6,1: 7,1: 8,1: 9,1: 10,1: 12 equal proportion with embodiment 9 similar approach.
The solid dispersion (1: 4) of embodiment 11. Entecavirs and Polyethylene Glycol, polyoxyethylene castor oil and preparation
Getting the 1g Entecavir is dissolved in the 90ml dimethyl formamide, add 1g polyethylene glycol 6000,3g polyoxyethylene castor oil in the ethanol of 60ml, fully stir, decompression is steamed ethanol and dimethyl formamide and is removed totally, vacuum drying is pulverized, and promptly obtains the solid dispersion of Entecavir and polyethylene glycol 6000, polyoxyethylene castor oil, wherein the mass ratio of Entecavir and polyethylene glycol 6000, polyoxyethylene castor oil is 1: 4, and the accumulative total dissolution is 94.31% during its 10min.
The solid dispersion (1: 9) of embodiment 12. Entecavirs and polyoxyethylene stearate (50) ester, polyoxyethylene castor oil and preparation
Get 1g Entecavir, 4g polyoxyethylene stearate (50) ester and 5g polyoxyethylene castor oil, place grinder, add the 70g distilled water, pastel is made in stirring, pastel is ground 30min, further remove and desolvate and drying, pulverize, promptly get the solid dispersion (1: 9) of Entecavir and carrier material.
Embodiment 13. contains the tablet and the preparation of the solid dispersion (1: 4) of Entecavir and Macrogol 4000
Entecavir/Macrogol 4000 solid dispersion (1: 4) 2.5g
Mannitol 130g
Pregelatinized Starch 70g
Carboxymethyl starch sodium 8g (in disintegrating agent)
Sodium lauryl sulphate 1g
Low-substituted hydroxypropyl cellulose 12g (adding disintegrating agent)
Magnesium stearate 1.5g
Preparation method one (wet granulation): by above prescription, preceding four kinds of pressed powder mixings are also crossed 80 mesh sieves, be dissolved in the liquid wet granulation of 80% alcoholic solution with sodium lauryl sulphate, the system soft material, 20 mesh sieves are granulated, and in 40 ℃ of dryings, the back adds pregelatinized Starch and magnesium stearate mix homogeneously, 18 mesh sieve granulate, tabletting (3.2kg/cm 2) be made as 1000, every contains active ingredient and counts 0.5mg with Entecavir, for orally using.The accumulative total dissolution is 95.85% during its 25min, and the disintegration of tablet time reached the quality scale requirement of dispersible tablet less than 140 seconds.
Preparation method two (dry granulation): the mannitol in the above-mentioned prescription; microcrystalline Cellulose; carboxymethyl starch sodium; the sodium lauryl sulphate adjuvant; pulverize; cross 80 mesh sieves; equivalent classification mixing; 45 ℃ through drying under reduced pressure more than 12 hours to constant weight; be cooled to room temperature at drying condition (in the exsiccator); take by weighing recipe quantity Entecavir/Macrogol 4000 solid dispersion and above-mentioned dry adjuvant; dry granulation behind the mix homogeneously (dry granulation machine); add pregelatinized Starch and magnesium stearate again; be compressed to 1000 behind the mix homogeneously, every contains active ingredient and counts 0.5mg with Entecavir, for orally using.The accumulative total dissolution is 93.27% during its 25min, reaches the quality scale requirement of dispersible tablet.
In addition, also can adopt conventional packaging technique that the tablet of above-mentioned preparation is carried out coating (gastric solubleness film-coat or enteric coating) and handle, can obtain the coating diaphragm.
Embodiment 14.
Similarly, by above method, select suitable pharmaceutic adjuvant for use, can make the tablet of the solid dispersion of Entecavir and glyceryl monostearate, Entecavir and polyoxyl stearate, Entecavir and sucrose fatty acid ester, Entecavir and polyoxyethylene castor oil respectively, the every content that can contain Entecavir is 0.2mg～1mg; The content of preferred Entecavir is 0.25mg, 0.5mg, 1mg.
Embodiment 15. contains the capsule and the preparation of the solid dispersion (1: 9) of Entecavir and glyceryl monostearate
The solid dispersion of Entecavir/glyceryl monostearate (1: 9) 5g
Starch 90g
Pulvis Talci 5g
To be filled into behind above-mentioned three kinds of solids mixings in 1000 Capsuleses (gastric solubleness or enteric) promptly.Every contains active ingredient and counts 0.5mg with Entecavir, for orally using.The accumulative total dissolution is 94.38% during capsule 's content 25min.
Embodiment 16. contains the capsule and the preparation of the solid dispersion (1: 8) of Entecavir and sucrose fatty acid ester
The solid dispersion of Entecavir/sucrose fatty acid ester (1: 8) 9g
Lactose 100g
Hydroxypropyl cellulose 30g
Carboxymethyl starch sodium 20g
Magnesium stearate 2g
Preparation: pulverized 80 mesh sieves after preceding four kinds of pressed powder equivalent of getting recipe quantity increase progressively mix homogeneously, mixing, to above-mentioned mixed-powder system soft material, 16 mesh sieves are granulated with 30% alcoholic solution, aeration-drying is filled into behind the 14 mesh sieve granulate in 1000 Capsuleses (gastric solubleness or enteric) promptly.Every contains active ingredient and counts 1mg with Entecavir, for orally using.
Similarly, by above method, select suitable pharmaceutic adjuvant for use, can make the capsule agent of the solid dispersion of Entecavir and glyceryl monostearate, Entecavir and polyoxyl stearate, Entecavir and Polyethylene Glycol, Entecavir and polyoxyethylene castor oil respectively, every content that can contain Entecavir is 0.2mg～1mg; The content of preferred Entecavir is 0.25mg, 0.5mg, 1mg.
Embodiment 1 7. contains the dry suspension and the preparation of Entecavir and polyoxyl stearate solid dispersion (1: 4)
Entecavir/polyoxyethylene stearate (40) ester solid dispersion (1: 4) 0.25g
Lactose 50g
Mannitol 40g
Icing Sugar 55g
Hydroxypropyl emthylcellulose 5g (suspending agent)
Flavoring orange essence is an amount of
Dehydrated alcohol is an amount of
Make 100 bags altogether.
Preparation method 1: it is dry respectively that the first five of side's amount planted pressed powder, to reduce the water content in the solid powder, get an amount of dehydrated alcohol, cross 20 mesh sieve wet granulations, granulate is put in 45 ℃ of baking ovens dry, spray wine flavoring orange essence, granulate is distributed into 100 bags of aluminum plastic film bag packings, promptly gets every bag of dry suspension (sweet Fructus Citri tangerinae taste) that contains Entecavir 0.5mg.
Preparation method 2: the above-mentioned pressed powder of recipe quantity is dry respectively, to reduce the water content in the solid powder, put the mixer moderate and increase progressively mix homogeneously, cross 100 mesh sieves, with 18 mesh sieve dry granulations, put 45 ℃ of oven dryings, spray wine flavoring orange essence, behind granulate, be distributed into 100 bags of aluminum plastic film bag packings, promptly get every bag of dry suspension (sweet Fructus Citri tangerinae taste) that contains Entecavir 0.5mg.The accumulative total dissolution is 91.83% during its 25min.
Embodiment 18. contains the granule and the preparation of Entecavir and polyoxyethylene castor oil solid dispersion (1: 3)
Entecavir/polyoxyethylene castor oil solid dispersion (1: 3) 0.2g
Lactose 70g
Pregelatinized Starch 15g
Icing Sugar 35g
Carboxymethyl starch sodium-starch (2: 8) 35g
Steviosin is an amount of
Flavoring orange essence is an amount of
30% alcoholic solution is an amount of
Make 100 bags altogether.
Preparation method 1: the first six of getting recipe quantity planted and to be pulverized 80 mesh sieves after pressed powder equivalent increases progressively mix homogeneously, mixing, steviosin and flavoring orange essence are dissolved in an amount of 30% alcoholic solution, to above-mentioned mixed-powder system soft material, 16 mesh sieves are granulated, aeration-drying with this solution, 14 mesh sieve granulate, be distributed into 100 bags of aluminum plastic film bag packings, promptly get the granule that contains Entecavir and polyoxyethylene castor oil solid dispersion (1: 3), every bag contains Entecavir 0.5mg (sweet Fructus Citri tangerinae taste).The accumulative total dissolution is 90.13% during its 25min.
Preparation method 2: the first six of getting recipe quantity planted and to be pulverized 80 mesh sieves after pressed powder equivalent increases progressively mix homogeneously, mixing, steviosin and flavoring orange essence are dissolved in the wetting agent of making wet granulation in an amount of 30% alcoholic solution, with the boiling granulating fluidized bed granulation, granulate, be distributed into 100 bags of aluminum plastic film bag packings, promptly contain the granule of Entecavir and polyoxyethylene castor oil solid dispersion (1: 3), every bag contains Entecavir 0.5mg (sweet Fructus Citri tangerinae taste).
Embodiment 19. contains the soft capsule and the preparation of Entecavir and glyceryl monostearate solid dispersion (1: 1)
Entecavir/glyceryl monostearate solid dispersion (1: 1) 1g
PEG400 240g
Glycerol 3g
Carboxymethyl starch sodium 5g
Make 1000 altogether.
Preparation method: get the Entecavir of recipe quantity and glyceryl monostearate solid dispersion (1: 1), PEG400 and propylene glycol heating in water bath to 43 ℃ and stir and make dissolving fully, obtain adding carboxymethyl starch sodium behind the clear and bright solution, dissolving stirs, stand-by, this clear and bright solution will be added to as the content of soft capsule in the continuously automatic soft capsule production machine of punching type, select appropriate mould model, adopt pressing to be embedded in the ' Yanming ' capsules for clearing material film, 1000 soft capsules are made in mold pressing, every contains Entecavir 0.5mg, for orally using.The accumulative total dissolution is 98.37% during its 25min.(also can adopt the dropping preparation method preparation)
(attached: the preparation of capsule material film, get gelatin 500g, arabic gum 80g, add 600～900ml distilled water, under room temperature, stir to quicken to make gelatin expansion post-heating to 55～60 ℃, make its fusion and filter, in filtrate, add 75g PEG400,370g glycerol, 10g glycine, mix homogeneously, decompression outgases to transparent glue solution does not have bubble, and repaste makes thickness even on smooth steel plate, heating makes surface moisture evaporation, is an elasticity, capsule material film that toughness is suitable.)
Embodiment 20. contains the drop pill and the preparation of Entecavir and polyoxyethylene stearate (40) ester solid dispersion (1: 49)
Entecavir/polyoxyethylene stearate (40) ester solid dispersion (1: 49) 200g
Sodium lauryl sulphate 5g
Crospolyvinylpyrrolidone 15g
Make 10000 altogether.
Preparation method: get Entecavir/polyoxyethylene stearate (40) ester solid dispersion (1: 27) heating in water bath to 53 of recipe quantity～55 ℃ complete fusion is in a liquid state, add recipe quantity sodium lauryl sulphate and crospolyvinylpyrrolidone, and fully stirring makes molten loosing in fused solution, stir, this fused solution is poured in the Materials hopper that drop pill drips the system machine, 55 ℃ of insulations, the water dropper of the suitable bore of selection drips makes 10000, splash in 4 ℃ the dimethicone, after to be formed, isolate drop pill, wiped clean, that is every heavily about 22mg.This drop pill can oral or sublingual administration use.
Embodiment 21. contains the drop pill and the preparation of Entecavir and glyceryl monostearate solid dispersion (1: 2)
Entecavir/glyceryl monostearate solid dispersion (1: 2) 3g
Polyethylene glycol 6000/Macrogol 4000 250g (equivalent is mixed and contained thing)
Sodium carboxymethyl cellulose 12g
Make 10000 altogether.
Preparation method: the equivalent of getting the polyethylene glycol 6000 of recipe quantity and Macrogol 4000 is mixed and is contained thing and be heated to 74 ℃ and make complete fusion be clear and bright liquid state, add recipe quantity Entecavir and glyceryl monostearate solid dispersion (1: 2) and fully stir and make molten loosing in the mixture of liquid state, the sodium carboxymethyl cellulose that adds recipe quantity again, stir, this fused solution is poured in the Materials hopper that drop pill drips the system machine, 72 ± 3 ℃ of insulations, the water dropper of the suitable bore of selection drips makes 10000, splash in 4 ℃ the dimethicone, to be formed after, isolate drop pill, wiped clean, that is, every heavily about 26mg contains the about 0.1mg of Entecavir.This drop pill can oral or sublingual administration use.The accumulative total dissolution is 95.71% during its 25min.
Further, above-mentioned drop pill branch can be packed in 400 Capsuleses (gastric solubleness or enteric) promptly, every capsules contains 5 drop pill, promptly get the drop pill capsule that contains Entecavir and glyceryl monostearate solid dispersion (1: 2), every drop pill capsule contains active ingredient and counts 0.5mg with Entecavir, for orally using.
Embodiment 22. contains the micropill and the preparation of Entecavir and sucrose fatty acid ester solid dispersion (1: 1)
Entecavir/sucrose fatty acid ester (HLB=11) solid dispersion (1: 1) 2g
Lactose 250g
Cane sugar powder 50g
Hydroxypropyl emthylcellulose 10g (binding agent)
Sodium carboxymethyl cellulose 10g
80% ethanol water is an amount of
Hydroxypropyl emthylcellulose 5g (sealing coat)
Preparation method: by above prescription, the first five is planted the pressed powder mixing and crosses 80 mesh sieves, with 80% alcoholic solution wet granulation, the system soft material, by extruding-rolling circle equipment system micropill, granulate, oven dry, make micropill be straight spherical shape through about 0.6mm, promptly obtain containing the micropill of Entecavir and sucrose fatty acid ester (HLB=11) solid dispersion (1: 1), further with hydroxypropyl methylcellulose with distilled water modulation into about 25% suspension, and fully grind homogenize after, at fluidized bed dryer, the sealing coat suspension is coated to above-mentioned containing on the pill core, after having applied the sealing coat suspension of aequum, with micropill bone dry in fluidized bed dryer, obtain the stomach dissolution type micropill of isolation coat, the accumulative total dissolution is 89.71% during its 25min.
Further, can be with the above-mentioned micropill that makes, divide in 2000 Capsuleses (gastric solubleness or enteric) of packing into, promptly get the pellet capsule that contains Entecavir and sucrose fatty acid ester (HLB=11) solid dispersion (1: 1), every pellet capsule contains active ingredient and counts 0.5mg with Entecavir, for orally using.
Embodiment 23. contains the micropill and the preparation of Entecavir and Macrogol 4000 solid dispersion (1: 4)
Entecavir/Macrogol 4000 solid dispersion (1: 4) 5g
Pregelatinized Starch 5g
Celphere: microcrystalline Cellulose-starch micropill (commercial, 35 to 40 orders) 150g
Opadry (water solublity) an amount of (sealing coat)
Preparation: Entecavir and Macrogol 4000 solid dispersion (1: 4), pregelatinized Starch are modulated suspension into about 20% with 70% ethanol water, and fully grinding homogenizes to reduce the suspension particle diameter, obtain containing the medicine layer coating solution of active ingredient, at fluidized bed dryer, the suspension that ground is coated on the celphere of microcrystalline Cellulose-starch micropill, after having applied the medicine layer coating solution of aequum, it is made it bone dry in fluidized bed dryer, the micropill that obtains.
Further, with Opadry with distilled water modulation into about 24～26% suspension, and after fully grinding homogenizes, at fluidized bed dryer, the sealing coat suspension spray is coated to above-mentioned containing on the pill core, after having applied the sealing coat suspension of aequum, with micropill bone dry in fluidized bed dryer, obtain the stomach dissolution type micropill of isolation coat, the accumulative total dissolution is 91.59% during its 25min.
Annotate: behind the Opadry that has applied aequum, micropill can be added a small amount of Pulvis Talci to reduce electrostatic charge when dry in fluidized bed dryer.
Further, the above-mentioned micropill that makes can be divided in 1000 Capsuleses (gastric solubleness or enteric) of packing into, promptly get the pellet capsule that contains the 1mg Entecavir, for orally using.
Embodiment 24. contains the oral fluid agent and the preparation of Entecavir and polyoxyethylene castor oil solid dispersion (1: 5)
Entecavir/polyoxyethylene castor oil solid dispersion (1: 5) 60mg
Hydroxypropyl cellulose 2g
Xylitol 10g
Sodium lauryl sulphate 0.8g
Potassium dihydrogen phosphate/sodium hydrogen phosphate an amount of (pH buffer agent)
Steviosin is an amount of
Water adds to 100ml
Preparation method: above-mentioned material is dissolved in the 80ml water, stirs, add water to 100ml, fully stir and homogenizing, promptly get the oral fluid agent that contains Entecavir and polyoxyethylene castor oil solid dispersion (1: 5).
The solid dispersion (1: 15) of embodiment 25. Entecavirs and Polyethylene Glycol, glyceryl monostearate and preparation
Getting 10g Polyethylene Glycol, 5g glyceryl monostearate simply mixes the back heating in water bath and makes it be fused liquid state for 60～63 ℃, fully stirring adds the 1g Entecavir after making mix homogeneously, fully stir and make mix homogeneously, be cooled to 5 ℃ and make curing, pulverize, and put 35 ℃ of dry 24h in the vacuum desiccator, and pulverized 80 mesh sieves, promptly get the solid dispersion (1: 15) of Entecavir and Polyethylene Glycol, glyceryl monostearate.The accumulative total dissolution is 97.43% during its 10min.
The solid dispersion and the preparation of embodiment 26. Entecavirs and glyceryl monostearate and carboxymethyl starch sodium
Entecavir 1g
Glyceryl monostearate 16g
Carboxymethyl starch sodium 3g
Preparation method: get Entecavir and glyceryl monostearate and be dissolved in 300ml, 40 ℃ the ethanol of heating in water bath, add carboxymethyl starch sodium, behind the stirring and evenly mixing on Rotary Evaporators reduction vaporization reclaim ethanol, collect solids, vacuum drying 15h, pulverize (crossing 80 mesh sieves), promptly get the solid dispersion of Entecavir and glyceryl monostearate and carboxymethyl starch sodium.The accumulative total dissolution is 97.05% during its 25min.
Solid dispersion and the preparation of embodiment 27. Entecavirs and polyoxyethylene stearate (40) ester and PEG6000
Entecavir 1g
Polyoxyethylene stearate (40) ester 6g
PEG6000 3g
Preparation method 1: three kinds of materials getting above-mentioned recipe quantity are dissolved in the 250ml dehydrated alcohol, stir back 40 ℃ and remove and reclaim ethanol under reduced pressure and obtain blocks of solid, put 24h in the vacuum constant temperature drying baker, take out after the embrittlement and pulverize, cross 80 mesh sieves, promptly get the solid dispersion of Entecavir and polyoxyethylene stearate (40) ester and PEG4000.
Preparation method 2: get polyoxyethylene stearate (40) ester of above-mentioned recipe quantity and PEG4000 and mix back heating in water bath to 55～58 ℃ and make its complete fusion, stir, the Entecavir that adds recipe quantity again, make molten loosing in the mixture of liquid state, fully mix, put refrigerator and spend the night for 0 ℃, pulverize, cross 80 mesh sieves, promptly get the solid dispersion of Entecavir and polyoxyethylene stearate (40) ester and PEG4000.
Get the solid dispersion and the preparation of embodiment 28. Entecavirs and sucrose fatty acid ester and microcrystalline Cellulose
Entecavir 1g
Sucrose fatty acid ester (HLB=12) 10g
Microcrystalline Cellulose 20g
Crospolyvinylpyrrolidone 5g
Preparation method: get above-mentioned material mixing, add 60% methanol-water solution 450ml, grind 30min, 40 ℃ of pressure reducing and steaming liquid are collected solids, vacuum drying 12h, be cooled to 0 ℃ of pulverizing (crossing 80 mesh sieves), promptly get the solid dispersion of Entecavir and sucrose fatty acid ester and microcrystalline Cellulose.
The solid dispersion and the preparation of embodiment 29. Entecavirs and polyoxyethylene castor oil and mannitol
Entecavir 1g
Polyoxyethylene castor oil 4g
Mannitol 40g
Preparation method: get above-mentioned three kinds of pressed powders and add in the 800ml ethanol (90%), fully stir and make its dissolving, 47 ℃ remove and reclaim ethanol (90%) under reduced pressure, collect solids, 35 ℃ of vacuum drying 24h, pulverize (crossing 80 mesh sieves), promptly get the solid dispersion of Entecavir and polyoxyethylene castor oil and mannitol.The accumulative total dissolution is 96.21% during its 25min.
Embodiment 30. gets the prepared solid dispersion of EXAMPLE Example 25, embodiment 26, embodiment 27, embodiment 28, embodiment 29 respectively, as principal agent, select suitable pharmaceutic adjuvant for use, adopt appropriate preparation technology, mix with pharmaceutic adjuvant and be prepared into and disperse sheet, slow releasing tablet, enteric coatel tablets, effervescent tablet, oral cavity disintegration tablet, chewable tablet, hard capsule, soft capsule, micropill, granule, dry suspension, powder, for orally using.
Embodiment 31. embodiment 1 to embodiment 40 prepared compositions, solid dispersion preparing the application for the treatment of in the hepatitis b virus infected medicine.

Claims (10)

1. the solid dispersion of an Entecavir, it is characterized in that containing Entecavir and carrier material, described carrier material is selected from one or more in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil, and the quality ratio range of Entecavir and carrier material is 1: (1～150).
2. the described solid dispersion of claim 1, the quality ratio range that it is characterized in that Entecavir and carrier material is 1: (1～140);
The quality ratio range of preferred Entecavir and carrier material is 1: (2～130);
The quality ratio range of preferred Entecavir and carrier material is 1: (3～120);
The quality ratio range of preferred Entecavir and carrier material is 1: (4～110);
The quality ratio range of preferred Entecavir and carrier material is 1: (5～100);
The quality ratio range of preferred Entecavir and carrier material is 1: (6～90);
The quality ratio range of preferred Entecavir and carrier material is 1: (7～80);
The quality ratio range of preferred Entecavir and carrier material is 1: (8～70);
The quality ratio range of preferred Entecavir and carrier material is 1: (9～60);
The quality ratio range of preferred Entecavir and carrier material is 1: (10～50);
The quality ratio range of preferred Entecavir and carrier material is 1: (1～50);
The quality ratio range of preferred Entecavir and carrier material is 1: (2～40);
The quality ratio range of preferred Entecavir and carrier material is 1: (3～30);
The quality ratio range of preferred Entecavir and carrier material is 1: (4～20);
The quality ratio range of preferred Entecavir and carrier material is 1: (3～20).
3. prepare the method for claim 1 or 2 described solid dispersion, it comprises:
Get Entecavir and carrier material, add solvent, in 20 ℃ to the scope of solvent boiling point temperature, stirring is dissolved or dispersed in the solvent Entecavir and carrier material, from this mixture, remove behind the mix homogeneously and desolvate, and the dry solid dispersion that obtains with pulverizing, wherein said carrier material selects Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more, described solvent is selected from water, dimethyl acetylamide, dimethyl formamide, methanol, ethanol, isopropyl alcohol, acetone, in the chloroform one or more, described remove desolvated and exsiccant method can be taked Rotary Evaporators to steam to remove, remove under reduced pressure, drying under reduced pressure, vacuum drying, lyophilization, spray drying, fluid bed drying, in the heating, drying one or more; Or
Get carrier material, add Entecavir in 50～90 ℃ after being heated to complete fusion, mix, cooling is pulverized after it is solidified, and promptly obtains solid dispersion, wherein said chilling temperature is below 25 ℃, preferred below 10 ℃, optionally can further the solid dispersion drying under reduced pressure be beneficial to pulverize and preserve, described carrier material is selected from one or more in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil; Or
Get carrier material in 50～90 ℃ be heated to complete fusion after, add water, dimethyl acetylamide, dimethyl formamide, methanol, ethanol, isopropyl alcohol, the dissolved Entecavir solution of acetone or chloroform, mix, remove and desolvate, and the dry solid dispersion that obtains with pulverizing, wherein said carrier material is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more, described remove desolvated and exsiccant method can be taked Rotary Evaporators to steam to remove, remove under reduced pressure, drying under reduced pressure, vacuum drying, lyophilization, spray drying, fluid bed drying, in the heating, drying one or more; Or
Entecavir and carrier material are made pastel with suitable liquid, pastel is ground, further remove liquid and dry, pulverize, promptly get the solid dispersion of Entecavir and carrier material, wherein said carrier material is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more, described liquid is selected from water, dimethyl acetylamide, dimethyl formamide, methanol, ethanol, isopropyl alcohol, acetone, chloroform, in the dichloromethane one or more, the amount of described liquid is Entecavir and carrier material total amount 3～15 times, and described liquid and the drying of removing can adopt and remove under reduced pressure, drying under reduced pressure, spray drying, lyophilization, fluid bed drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
Get Entecavir and carrier material, put in the mortar and grind, 100～600 rev/mins of rotating speeds, milling time 10～150min, take out, cross 80～200 mesh sieves, promptly get the solid dispersion of Entecavir and carrier material, wherein said carrier material is selected from one or more in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil;
In the above-mentioned preparation method, the mode of described grinding can be carried out in such as grinder, extruder, homogenizer or blade blender.
4. one kind contains Entecavir and one or more the solid dispersion that is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil, it is characterized in that it is made by following method:
Get Entecavir and carrier material, add solvent, in 20 ℃ to the scope of solvent boiling point temperature, stirring is dissolved or dispersed in the solvent Entecavir and carrier material, from this mixture, remove behind the mix homogeneously and desolvate, and the dry solid dispersion that obtains with pulverizing, wherein said carrier material selects Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more, described solvent is selected from water, dimethyl acetylamide, dimethyl formamide, methanol, ethanol, isopropyl alcohol, acetone, in the chloroform one or more, described remove desolvated and exsiccant method can be taked Rotary Evaporators to steam to remove, remove under reduced pressure, drying under reduced pressure, vacuum drying, lyophilization, spray drying, fluid bed drying, in the heating, drying one or more; Or
Get carrier material, add Entecavir in 50～90 ℃ after being heated to complete fusion, mix, cooling is pulverized after it is solidified, and promptly obtains solid dispersion, wherein said chilling temperature is below 25 ℃, preferred below 10 ℃, optionally can further the solid dispersion drying under reduced pressure be beneficial to pulverize and preserve, described carrier material is selected from one or more in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil; Or
Get carrier material in 50～90 ℃ be heated to complete fusion after, add water, dimethyl acetylamide, dimethyl formamide, methanol, ethanol, isopropyl alcohol, the dissolved Entecavir solution of acetone or chloroform, mix, remove and desolvate, and the dry solid dispersion that obtains with pulverizing, wherein said carrier material is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more, in above-mentioned preparation, described remove desolvated and exsiccant method can be taked Rotary Evaporators to steam to remove, remove under reduced pressure, drying under reduced pressure, vacuum drying, lyophilization, spray drying, fluid bed drying, in the heating, drying one or more; Or
Entecavir and carrier material are made pastel with suitable liquid, pastel is ground, further remove liquid and dry, pulverize, promptly get the solid dispersion of Entecavir and carrier material, wherein said carrier material is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, in the polyoxyethylene castor oil one or more, described liquid is selected from water, dimethyl acetylamide, dimethyl formamide, methanol, ethanol, isopropyl alcohol, acetone, chloroform, in the dichloromethane one or more, the amount of described liquid is Entecavir and carrier material total amount 3～15 times, and described liquid and the drying of removing can adopt and remove under reduced pressure, drying under reduced pressure, spray drying, lyophilization, fluid bed drying, heating, drying, air-dry or noble gas is dry or its combination in any method concentrates and dry; Or
Get Entecavir and carrier material, put in the mortar and grind, 100～600 rev/mins of rotating speeds, milling time 10～150min, take out, cross 80～200 mesh sieves, promptly get the solid dispersion of Entecavir and carrier material, wherein said carrier material is selected from one or more in Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil;
In the above-mentioned preparation method, the mode of described grinding can be carried out in such as grinder, extruder, homogenizer or blade blender.
5. claim 1,2 or 4 described solid dispersion contain application in the pharmaceutical preparation of Entecavir in preparation; Application in the hepatitis b virus infected medicine of preparation treatment.
6. a pharmaceutical composition contains claim 1,2 or 4 described solid dispersion and pharmaceutically suitable carrier, and wherein in unit formulation, the content of the Entecavir that solid dispersion provided of Entecavir is 0.2mg～10mg;
The content of preferred Entecavir is 0.25mg～5mg;
The content of preferred Entecavir is 0.5mg～1mg.
7. the method for preparing the described pharmaceutical composition of claim 6, it comprises Entecavir and one or more solid dispersion and the pharmaceutically suitable carrier that is selected from Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil fully is mixed and made into acceptable any pharmaceutical dosage form on the pharmaceutics that preferred pharmaceutical dosage form is tablet, hard capsule, soft capsule, drop pill, pellet, granule, dry suspension, powder, oral fluid agent, injection.
8. prepare the method for the described pharmaceutical composition of claim 6, it comprises:
By adopting wet granulation or dry granulation to obtain granule or dry suspension behind the solid dispersion of Entecavir of the present invention and the pharmaceutical carrier mix homogeneously, optionally further tabletting obtains tablet or the fill Capsules obtains capsule, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
By obtaining dry suspension or powder behind the solid dispersion of Entecavir and the pharmaceutical carrier mix homogeneously, optionally can further dry suspension or powder fill Capsules shell be obtained hard capsule, perhaps mix homogeneously obtains granule behind wet granulation or the dry granulation, to obtain hard capsule in the granule fill Capsules shell, wherein the solid medicinal carrier includes but not limited to the following material as filler or diluent: lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), include but not limited to following material: hydroxypropyl emthylcellulose as the suspending agent of dry suspension, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose includes but not limited to the following material as lubricant: magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate; Or
By obtaining soft capsule with dripping to make to seal with soft capsule material compacting of gelatin or capsule material glue behind the solid dispersion of Entecavir and the suitable pharmaceutical carrier mix homogeneously, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: Liquid Macrogol, PEG400, Macrogol 600, soybean oil, Semen Maydis oil, other vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described " soft capsule material compacting or the capsule material glue system of dripping are sealed " is meant and adopts pressing or dropping preparation method to prepare soft capsule, pressing is meant that the liquid or soft plastic state content that adopts press will contain solid dispersion wraps up formation preparation of soft capsule method with the compacting of capsule material film, can be pressed into different shapes and content content with different moulds, usually seal the capsule preparation with rotating the continuously automatic soft capsule production machine of rolling capsule machine or punching type automatically, dropping preparation method is meant the method that is equipped with soft capsule by a making mechanism, at a certain temperature, generally remain on more than 45 ℃, it is biphase utilizing capsule material glue and liquid content, after making a certain amount of capsule material glue with quantitative liquid content parcel, splash into that (condensed fluid can be a liquid paraffin in the another kind of not miscible condensed fluid, methyl-silicone oil, vegetable oil, in the kerosene any one), behind the capsule material glue condensation by contact liquid, owing to surface tension effects makes it to solidify the spherical soft capsule of formation; Or
By with Entecavir and Polyethylene Glycol, glyceryl monostearate, after the solid dispersion melting mixing of polyoxyl stearate is even, or with Entecavir and Polyethylene Glycol, glyceryl monostearate, after the mixture melting mixing of polyoxyl stearate is even, splash in the not miscible condensed fluid, shrink condensation and make drop pill, optionally drop pill can contain but be not limited to following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, can contain but be not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth), described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with the solid dispersion of Entecavir and suitable pharmaceutical carrier melting mixing evenly after, splash in the not miscible condensed fluid, shrink condensation and make drop pill, wherein pharmaceutical carrier includes but not limited to the following material as filler or diluent: cetomacrogol 1000, polyethylene glycol 1500, Macrogol 3000, Macrogol 4000, Polyethylene Glycol 5000, polyethylene glycol 6000, Polyethylene Glycol 7000, Polyethylene Glycol 8000, Polyethylene Glycol 9000, cetomacrogol 1000 0, stearic acid, sodium stearate, hydrogenated vegetable oil, include but not limited to following material: sodium carboxymethyl cellulose as disintegrating agent, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, pregelatinized Starch, corn starch, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, described condensed fluid includes but not limited to dimethicone, liquid paraffin, vegetable oil (as Semen Maydis oil), kerosene obtains the drop pill capsule in the capsulae vacuus of optionally can further drop pill being packed into; Or
By with behind the solid dispersion of Entecavir and the suitable pharmaceutical carrier mix homogeneously, make the solid preparation of spherical or near-spherical, perhaps with the solid dispersion of Entecavir and suitable pharmaceutical carrier dissolving or molten being dispersed in the liquid medium, and its deposition is coated on the surface of celphere and forms micropill, wherein the solid medicinal carrier includes but not limited to the following material as disintegrating agent: sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium, include but not limited to following material: polyvinylpyrrolidone as binding agent, starch slurry, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum, or the like, include but not limited to following material: sodium lauryl sulphate as surfactant, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth) obtains the drop pill capsule in the capsulae vacuus of optionally can further micropill being packed into; Or
By the solid dispersion of Entecavir and water or aqueous liquid mixing are evenly formed oral administration solution or suspension; Or
By solid dispersion and suitable injection pharmaceutical carrier mix homogeneously with Entecavir, can obtain injection by the injection preparation method, wherein pharmaceutical carrier includes but not limited to the following material as filler or excipient: water, mannitol, sorbitol, lactose, xylitol, fructose, dextran, glucose, sodium chloride.
9. the solid dispersion of an Entecavir, contain Entecavir, carrier material and other pharmaceutical carrier, wherein the quality ratio range of Entecavir and carrier material is 1: (1～150), and described carrier material is selected from one or more in polyvinylpyrrolidone, poloxamer, Polyethylene Glycol, glyceryl monostearate, polyoxyl stearate, sucrose fatty acid ester, the polyoxyethylene castor oil; And described other pharmaceutical carrier includes but not limited to lactose, mannitol, sorbitol, microcrystalline Cellulose, starch, modified starch, dextrin, cyclodextrin and derivant thereof, calcium phosphate, sucrose, Polyethylene Glycol (various molecular weight polyethylene glycol), pregelatinized Starch, xylitol, fructose, maltose alcohol, dextran, glucose, calcium sulfate, calcium hydrogen phosphate as filler or diluent; Include but not limited to sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, pregelatinized Starch, corn starch, crosslinked carboxymethyl fecula sodium, microcrystalline Cellulose, carboxymethylcellulose calcium as disintegrating agent; Include but not limited to sodium lauryl sulphate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium stearyl sulfate, Polysorbate (Polysorbate of various models), fatty acid Pyrusussuriensis smooth (the fatty acid Pyrusussuriensis of various models is smooth) as surfactant; Include but not limited to hydroxypropyl emthylcellulose, ethyl cellulose, arabic gum, xanthan gum, sodium carboxymethyl cellulose as suspending agent; Include but not limited to methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum, xanthan gum as binding agent; Include but not limited to magnesium stearate, stearic acid, Pulvis Talci, stearyl fumarate as lubricant.
10. the method for preparing the described solid dispersion of claim 9, it comprises Entecavir, carrier material and other pharmaceutical carrier fully is mixed and made into any pharmaceutical dosage form of acceptable on the pharmaceutics that preferred pharmaceutical dosage form is tablet, hard capsule, soft capsule, drop pill, pellet, granule, dry suspension, powder, oral fluid agent, injection.
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Cited By (3)

* Cited by examiner, † Cited by third party
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WO2010143199A1 (en) * 2009-06-11 2010-12-16 Suven Nishtaa Pharma Private Limited Solid lipid dispersion for aqueous solubility enhancement of poorly water soluble drugs
CN105055353A (en) * 2015-09-02 2015-11-18 山东新时代药业有限公司 Entecavir tablets and preparation method thereof
CN106727339A (en) * 2016-12-23 2017-05-31 湖南千金协力药业有限公司 A kind of entecavir solid dispersion and a kind of Entecavir formulation

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KR101633292B1 (en) * 2014-02-25 2016-06-24 동아에스티 주식회사 Pharmaceutical composition containing entecavir with improved usage
WO2015130083A1 (en) * 2014-02-25 2015-09-03 동아에스티 주식회사 Pharmaceutical composition with improved usage containing entecavir

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010143199A1 (en) * 2009-06-11 2010-12-16 Suven Nishtaa Pharma Private Limited Solid lipid dispersion for aqueous solubility enhancement of poorly water soluble drugs
CN105055353A (en) * 2015-09-02 2015-11-18 山东新时代药业有限公司 Entecavir tablets and preparation method thereof
CN105055353B (en) * 2015-09-02 2018-05-11 山东新时代药业有限公司 A kind of Entecavir tablet and preparation method thereof
CN106727339A (en) * 2016-12-23 2017-05-31 湖南千金协力药业有限公司 A kind of entecavir solid dispersion and a kind of Entecavir formulation

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