CN103330944A - Bicyclol oral solid pharmaceutical composition, and preparation and preparation method thereof - Google Patents
Bicyclol oral solid pharmaceutical composition, and preparation and preparation method thereof Download PDFInfo
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- CN103330944A CN103330944A CN201310228976XA CN201310228976A CN103330944A CN 103330944 A CN103330944 A CN 103330944A CN 201310228976X A CN201310228976X A CN 201310228976XA CN 201310228976 A CN201310228976 A CN 201310228976A CN 103330944 A CN103330944 A CN 103330944A
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Abstract
The invention relates to a bicyclol oral solid pharmaceutical composition which comprises an active component bicyclol and a medicinal adjuvant, wherein the medicinal adjuvant comprises a solubilizer and a filler, the solubilizer accounts for 0.2-5 times by weight of the bicyclol, and the filler accounts for 3-50 times by weight of the bicyclol. The invention also relates to an oral solid preparation prepared from the pharmaceutical composition and a preparation method thereof. The oral solid preparation provided by the invention has higher bioavailability than the common bicyclol tablets in the market, has the advantages of high disintegration speed, high dissolution, simple preparation technique and cheap and accessible adjuvant, and can easily implement industrial production.
Description
Technical field
The invention belongs to field of medicine preparing technology, be specifically related to a kind of bicyclol oral solid drug composition, preparation and preparation method.
Background technology
Bicyclol is the anti-hepatitis original new drug with independent intellectual property right of institute of Materia Medica,Chinese Academy of Medical Sciences development, and 16 patented protections in countries and regions, the dosage form of going on the market at present is conventional tablet.Bicyclol raw material and tablet thereof obtained New Drug Certificate and produce official written reply in calendar year 2001, were produced without competition by the Beijing XieHe medicine Factory.Bicyclol is used for the treatment of chronic hepatitis, can obviously improve liver function, transaminase lowering, has certain antiviral effect simultaneously, is difficult for bounce-back after the drug withdrawal, and safety is good.Through Beijing, Shanghai Duo Jia hospital 500 many cases chronic viral hepatitis Bs, hepatitis C patient carry out clinical observation on the therapeutic effect, show that this medicine not only can reduce serum glutamic pyruvic transminase and glutamic oxaloacetic transaminase, GOT, and have the effect that certain inhibition hepatovirus copies, and do not find apparent side effect.But because bicyclol water solublity and fat-soluble all relatively poor influences the stable performance of its bioavailability and curative effect.
In view of the good market prospect of bicyclol and the deficiency of existing preparation, press for clinically that exploitation bioavailability height, individual variation are little, the new formulation of stable curative effect, to satisfy different patients' treatment needs.
The Beijing XieHe medicine Factory has developed pharmaceutical composition and preparation method thereof and the preparation (granted patent ZL200810117846.8) that bicyclol contains surfactant, a kind of is pharmaceutical composition and the preparation relevant patented technologies such as (granted patent ZL201010554865.4) thereof of active component with the bicyclol, by bicyclol is dissolved in by surfactant, cosurfactant, in the medicine carrying substrate that one or more one-tenth in the oils are grouped into, prepare a kind of pharmaceutical composition, be used for oral administration, pass through self emulsifying, mechanism such as self-emulsifying microemulsion or solubilising, can in pipe intestinal digesting liquid, realize microemulsified or dissolving, thereby significantly improve the bioavailability of bicyclol.But aforementioned pharmaceutical compositions is liquid or semisolid, and its comparatively suitable dosage form is the oil capsule preparation, and production equipment is had higher requirement, and phenomenons such as leakage appear in product easily in storage and transportation.
Therefore, exploitation obtains the high oral solid formulation that contains bicyclol of bioavailability, is the important topic that the bicyclol new preparation developing faces.
Summary of the invention
At the defective that exists in the prior art, an object of the present invention is to provide a kind of bicyclol oral solid drug composition, this pharmaceutical composition disintegration rate is fast, dissolution height, bioavailability height.
Another object of the present invention provides the oral solid formulation of being made by aforementioned pharmaceutical compositions, and this oral solid formulation has higher bioavailability than listing common double cyclic alcohol tablet, and disintegration rate is fast, the dissolution height.
The 3rd purpose of the present invention provides the preparation method of above-mentioned oral solid formulation, and its technology is simple, and adjuvant is cheap and easy to get, is easy to suitability for industrialized production.
For reaching above purpose, the technical solution used in the present invention is: a kind of bicyclol oral solid drug composition, comprise active component bicyclol and pharmaceutically acceptable auxiliaries, comprise solubilizing agent in the pharmaceutically acceptable auxiliaries, pharmaceutically acceptable auxiliaries also comprises filler, the weight of solubilizing agent is 0.2～5 times of bicyclol weight, and the weight of filler is 3～50 times of bicyclol weight.
The dosage range of active component bicyclol can be per unit preparation 4mg～100mg in the described pharmaceutical composition, preferred per unit preparation 10mg～50mg.Certainly, can also adopt wider dosage according to special needs, specifically can adjust according to the needs of clinical application.
Further, the weight of solubilizing agent is 0.3～3 times of bicyclol weight.
Further, solubilizing agent is selected from one or more in Polysorbate, polyoxyethylene castor oil, Polyethylene Glycol, polyoxyethylene hydroxy stearic acid ester, the polyoxyethylene polyoxypropylene block copolymer.
Further again:
Described Polysorbate is Tween 80 and/or polysorbate60, preferred Tween 80.
Described polyoxyethylene castor oil is the poly-hydrocarbon oxygen ester 35(Cremophor EL of polyoxyethylene hydrogenated Oleum Ricini (Cremophor RH40) and/or Oleum Ricini), be preferably Cremophor RH40.
Described Polyethylene Glycol is selected from one or more of PEG200, PEG400, PEG600, is preferably PEG400.
The preferred polyoxyethylene 12-of described polyoxyethylene hydroxy stearic acid ester hydroxy stearic acid ester 15(Solutol HS15).
The preferred poloxamer 188 of described polyoxyethylene polyoxypropylene block copolymer.
Further, filler is selected from one or more in microcrystalline Cellulose (MCC), low-substituted hydroxypropyl cellulose (L-HPC), starch, pregelatinized Starch, dextrin, lactose, sucrose, mannitol, calcium hydrogen phosphate, the calcium sulfate etc.
The adding of filler, purpose is to improve the solid content of compositions, make and be convenient to prepare suitable oral solid formulation, the consumption of described filler is 3～50 times of bicyclol consumption, certainly, if weight of formulation, outward appearance or mouldability etc. are not had conventional requirement, the consumption of described filler also can exceed the scope of above-mentioned consumption.
Further, pharmaceutically acceptable auxiliaries also comprises disintegrating agent, binding agent, lubricant, fluidizer, suspending agent, stabilizing agent and can modify in the additive of sense organ one or more.
Further again:
Described disintegrating agent is selected from one or more in carboxymethyl starch sodium (CMS-Na), crospolyvinylpyrrolidone (PVPP), cross-linking sodium carboxymethyl cellulose (CCMC-Na), the low-substituted hydroxypropyl cellulose (L-HPC).
The adding of disintegrating agent, purpose are to improve the diffusing speed of collapsing of compositions, thereby more are conducive to quick release and the absorption of medicine.In the aforementioned filler, some namely has good disintegrating property as filleies itself such as MCC, L-HPC, starch, so the adding of described disintegrating agent not necessarily.Usually, if add disintegrating agent, the consumption of described disintegrating agent can be 0.1～2 times of bicyclol consumption, and preferable amount is 0.1～1 times of bicyclol consumption.
Described binding agent is selected from the starch slurry of the water of hydroxypropyl methylcellulose (HPMC) of water, alcoholic solution, 3～10wt% or alcoholic solution, 5～10wt%, in the gelatine size one or more.Binding agent is preferably water or the alcoholic solution of the hydroxypropyl methylcellulose (HPMC) of water, alcoholic solution, 3～10wt%.
Described lubricant is selected from one or more in stearate (as magnesium stearate, calcium stearate, zinc stearate, stearic acid etc.), Pulvis Talci, silicate (as silicon dioxide, micropowder silica gel, aluminium-magnesium silicate etc.), fumarate (as fumaric acid sodium, fumaric acid etc.), Polyethylene Glycol, the grease compounds (as hydrogenated vegetable oil, sodium laurylsulfate, magnesium laurylsulfate, polyoxyethylene monostearate etc.).Lubricant is preferably stearate or Pulvis Talci.
Described fluidizer is with aforementioned lubricant, because in pharmaceutically the two not differentiation of strictness usually.The adding of above-mentioned lubricant and/or fluidizer, its purpose are to improve the flowability of compositions when formulation preparation such as tabletting or packing, and those skilled in the art can determine to add or do not add as required, and what of addition.
Described suspending agent is selected from one or more in sodium alginate, agar, sodium carboxymethyl cellulose, the glycerol etc.
Described stabilizing agent can be antioxidant, such as being selected from sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, vitamin C, butylated hydroxyarisol, dibutyl phenol, propyl gallate, tocopherol, ascorbic acid, the cetylate one or more.
The described additive that can modify sense organ is selected from one or more of malic acid, fumaric acid, vanillin, Mentholum or other suitable pigments, essence.
When using above-mentioned adjuvant or additive, its consumption pharmaceutically is being allowed in the acceptable scope, and does not exceed the protection domain of pharmaceutical composition provided by the present invention.
The present invention also provides by the made oral solid formulation of above-mentioned bicyclol oral solid drug composition, and described oral solid formulation can be tablet, granule, capsule or packed electuary.
The present invention also provides the preparation method by the made oral solid formulation of the solid composite medicament that mainly contains bicyclol, solubilizing agent, filler, is selected from one of following method:
Wet granulation, method one: bicyclol and solubilizing agent be molten addition method altogether, is applicable to liquid state or semisolid solubilizing agent, may further comprise the steps:
(1) preparation is total to molten thing: take by weighing solubilizing agent and bicyclol by proportioning, mix homogeneously makes dissolving under the condition that is no more than 100 ℃ of heating;
(2) wet granulation: take by weighing filler by proportioning, add the common molten thing that step (1) obtains, mix homogeneously is granulated drying;
(3) make preparation: the particulate matter tabletting that step (2) is obtained or direct packaging obtain being suitable for oral preparation in hard capsule, packaging bag;
Wet granulation, method two: the independent addition method of solubilizing agent, be applicable to liquid state or semisolid solubilizing agent, may further comprise the steps:
1) preparation pastille mixture: take by weighing bicyclol and filler, mix homogeneously by proportioning;
2) wet granulation: take by weighing solubilizing agent by proportioning, join in the pastille mixture that step 1) obtains, mix homogeneously is granulated drying;
3) make preparation: with step 2) the particulate matter tabletting that obtains or direct packaging in hard capsule, packaging bag, obtain being suitable for oral preparation;
Full pressed powder or packing, method three: be applicable to the solubilizing agent of solid state powder shape, may further comprise the steps:
Take by weighing bicyclol and all adjuvants by proportioning, mix homogeneously, direct compression or direct packaging obtain being suitable for oral preparation in hard capsule, packaging bag.
The present invention also provides the preparation method of the oral solid formulation that contains other adjuvants, can be selected from one of following method:
Wet granulation, method one: bicyclol and solubilizing agent be molten addition method altogether, is applicable to liquid solubilizers such as Tween 80 etc. or semisolid solubilizing agent such as Cremophor RH40 etc., may further comprise the steps:
(1) preparation is total to molten thing: take by weighing solubilizing agent and bicyclol by proportioning, mix homogeneously makes dissolving under the condition that is no more than 100 ℃ of heating;
(2) wet granulation: take by weighing the disintegrating agent that adds in partly or entirely being used for of filler and survival dose and other adjuvants except binding agent, lubricants of survival dose by proportioning, mix homogeneously, add the common molten thing that step (1) obtains, mix homogeneously, the binding agent that adds survival dose again, mixing granulation, drying;
(3) make preparation: add the lubricants of remaining disintegrating agent and survival dose in the particulate matter that obtains to step (2), mix homogeneously, tabletting or direct packaging obtain being suitable for oral preparation in hard capsule, packaging bag;
Wet granulation, method two: the independent addition method of solubilizing agent, be applicable to liquid solubilizers such as Tween 80 etc. or semisolid solubilizing agent such as Cremophor RH40 etc., may further comprise the steps:
1) preparation pastille mixture: take by weighing the disintegrating agent that adds in partly or entirely being used for of bicyclol, filler and survival dose and other adjuvants except binding agent, lubricants of survival dose, mix homogeneously by proportioning;
2) wet granulation: take by weighing solubilizing agent by proportioning, join in the pastille mixture that step 1) obtains, mix homogeneously adds the binding agent of survival dose again, and mix homogeneously is granulated drying;
3) make preparation: to step 2) add the lubricants of remaining disintegrating agent and survival dose in the particulate matter that obtains, mix homogeneously, tabletting or direct packaging obtain being suitable for oral preparation in hard capsule, packaging bag;
Full pressed powder or packing, method three: be applicable to the solubilizing agent of solid state powder shape such as poloxamer 188 etc., may further comprise the steps:
Take by weighing bicyclol and all adjuvants by proportioning, mix homogeneously, direct compression or direct packaging obtain being suitable for oral preparation in hard capsule, packaging bag.
In said method provided by the invention, when preparation is total to molten thing in the step (1) of method one, can add proper amount of diluting in case of necessity, alcoholic solution as 50～95v/v%, binding agent used when perhaps adding an amount of granulation dilutes, join again in other adjuvants behind the mix homogeneously, be beneficial to mixing of materials and be uniformly dispersed.Similarly, step 2 at method two) in, before adding solubilizing agent, can in solubilizing agent, add proper amount of diluting earlier, alcoholic solution as 50～95v/v%, binding agent used when perhaps adding an amount of granulation dilutes, and joins in the pastille mixture behind the mix homogeneously again, is beneficial to mixing of materials and is uniformly dispersed.
Above-mentioned three kinds of different preparation methoies provided by the invention, those skilled in the art can select for use according to suitable situation, studies show that, and its preparation preparation all can reach the effect that improves the bicyclol oral administration biaavailability.
In addition, produced according to the present invention obtain above-mentioned dosage form after, those skilled in the art can also carry out coating to tablet, granule, capsule etc. as required, or carries out other forms of packing or packing, this does not all exceed the protection domain that the present invention comprises.
The present invention has following beneficial effect:
The first, improved the dissolution of preparation.
Adopt the solubilizing agent of kind described in the present invention and consumption, itself can make bicyclol dissolving or congruent melting under the condition of suitably heating, it is added in the preparation prescription, thereby make the preparation for preparing improve the dissolution of bicyclol greatly than common solid preparation.
The second, improved the bioavailability of preparation.
The bicyclol oral solid formulation that adopts technical scheme of the present invention to prepare, disintegrate is rapid, and the dissolution height has improved the absorbent properties of bicyclol simultaneously, thereby improves the bioavailability of bicyclol greatly than common solid preparation.Experiment shows, adopts different prescription of the present invention under the condition that contains bicyclol 10mg～15mg/ sheet, can reach the effect (seeing embodiment 10) of the bioavailability identical with the conventional tablet that contains bicyclol 25mg of present listing.
The raising of bioavailability, not only expection improves the clinical efficacy of bicyclol, can reduce the consumption of bicyclol raw material simultaneously, is conducive to reduce the financial burden of patient's medication.
Three, the present invention has obtained the suitable amount ranges of solubilizing agent suitable in the bicyclol oral solid formulation and suitable adding method by experiment, can guarantee that supplementary material is uniformly dispersed, make the preparation that is suitable for the solid preparation product, and the preparation method technology that it provides is simple, controllability is good, adjuvant is cheap and easy to get, is easy to suitability for industrialized production.
Description of drawings
Fig. 1 contains bicyclol 10mg/ sheet for the oral bicyclol embodiment 2(of the present invention of Beagle dog) tablet, embodiment 3(contain bicyclol 15mg/ sheet) tablet and listing bicyclol conventional tablet (containing bicyclol 25mg/ sheet) back blood drug level-time graph comparison diagram, wherein curve A is represented the blood drug level-time graph of the tablet of embodiment 2; Curve B is represented the blood drug level-time graph of the tablet of embodiment 3; Curve C represent the to go on the market blood drug level-time graph of bicyclol conventional tablet.
The specific embodiment
Below in conjunction with drawings and Examples the present invention is further described.
Reagent among the embodiment all can be buied from market.
Embodiment 1
Component and proportioning see Table 1.
Table 1
Preparation method one:
(1) preparation is total to molten thing: the proportioning by table 1 takes by weighing the solubilizing agent Tween 80, adds the bicyclol of recipe quantity, adds the medicinal alcohol solution 50ml of diluent 95v/v%, and mix homogeneously stirs under the condition of 50 ℃ of heating and makes dissolving;
(2) wet granulation: the proportioning by table 1 takes by weighing filler MCC PH101 and disintegrating agent CMS-Na, mix homogeneously; Add the resulting molten thing altogether of step (1), mix homogeneously; Adding concentration is the purification of aqueous solutions 40ml of the HPMC of 3wt%, mixing granulation, and 60 ℃ of dryings obtain the bicyclol medicine-containing particle;
(3) make preparation: add magnesium stearate lubricant to above-mentioned containing in the bicyclol medicine-containing particle, mix homogeneously is sub-packed in the hard capsule, and specification contains bicyclol 5mg/ grain.
Preparation method two:
1) preparation pastille mixture: the proportioning by table 1 takes by weighing active component bicyclol, filler MCC PH101 and disintegrating agent CMS-Na, mix homogeneously;
2) wet granulation: the proportioning by table 1 takes by weighing the solubilizing agent Tween 80, adds 60v/v% medicinal alcohol solution 90ml, mix homogeneously, and 50 ℃ of heated and stirred make dissolving, join then in the pastille mixture that step 1) obtains, and mix homogeneously is granulated; 60 ℃ of dryings prepare the bicyclol medicine-containing particle;
3) make preparation: with the step (3) of preparation method one.
Embodiment 2
Component and proportioning see Table 2.
Table 2
Preparation method one:
(1) preparation is total to molten thing: the proportioning by table 2 takes by weighing solubilizing agent Tween 80, Cremophor RH40, adds the recipe quantity bicyclol, adds diluent 80v/v% ethanol 40ml, and mix homogeneously stirs under the condition of 80 ℃ of heating and makes dissolving;
(2) wet granulation: the proportioning by table 2 takes by weighing filler starch and L-HPC and disintegrating agent PVPP, mix homogeneously; Add the common molten thing that step (1) obtains, mix homogeneously; The 60v/v% alcoholic solution 30ml that with concentration is 5wt%HPMC is binding agent, mixing granulation, and 60 ℃ of dryings obtain the bicyclol medicine-containing particle;
(3) make preparation: in above-mentioned bicyclol medicine-containing particle, add fluidizer micropowder silica gel, magnesium stearate lubricant, mix homogeneously, tabletting, specification contains bicyclol 10mg/ sheet.
Preparation method two:
1) preparation pastille mixture takes by weighing active component bicyclol and filler starch, L-HPC and disintegrating agent PVPP, mix homogeneously by the proportioning of table 2;
2) wet granulation: the proportioning by table 2 takes by weighing solubilizing agent Tween 80, Cremophor RH40, adds 60v/v% medicinal alcohol 70ml, mix homogeneously, and heated and stirred makes dissolving, joins then in the pastille mixture that step 1) obtains, and mix homogeneously is granulated; 60 ℃ of dryings prepare the bicyclol medicine-containing particle;
3) make preparation: with the step (3) of preparation method one.
Component and proportioning see Table 3.
Table 3
Preparation method one:
(1) preparation is total to molten thing: the proportioning by table 3 takes by weighing solubilizing agent Cremophor RH40 and PEG400, adds the bicyclol of recipe quantity, adds diluent 95v/v% medicinal alcohol solution 40ml again, and mix homogeneously stirs under the condition of 80 ℃ of heating and makes dissolving;
(2) wet granulation: the proportioning by table 3 takes by weighing filler MCC and lactose, mix homogeneously; Add the common molten thing that step (1) obtains, mix homogeneously; Add 60v/v% ethanol 50ml, mixing granulation, 60 ℃ of dryings prepare the bicyclol medicine-containing particle;
(3) make preparation: in above-mentioned bicyclol medicine-containing particle, add disintegrating agent CMS-Na, lubricant Pulvis Talci, mix homogeneously, tabletting, specification contains bicyclol 15mg/ sheet.
Preparation method two:
1) preparation pastille mixture: take by weighing active component bicyclol and filler MCC, lactose, mix homogeneously by the proportioning of table 3;
2) wet granulation: the proportioning by table 3 takes by weighing solubilizing agent Cremophor RH40 and PEG400, adds 60v/v% medicinal alcohol solution 70ml, mix homogeneously, and 80 ℃ of heated and stirred make dissolving, join in the pastille mixture that step 1) obtains mixing granulation then; 60 ℃ of dryings obtain the bicyclol medicine-containing particle;
3) make preparation: with the step (3) of preparation method one.
Embodiment 4
Component and proportioning see Table 4.
Table 4
| Component | 1000 dosage amounts (g) |
| Bicyclol | 25 |
| Tween 80 | 10 |
| Starch | 70 |
| Icing Sugar | 30 |
| CMS- |
3 |
| PVPP | 7 |
| Magnesium stearate | 0.4 |
Preparation method one:
(1) preparation is total to molten thing: the proportioning by table 4 takes by weighing the solubilizing agent Tween 80, adds the recipe quantity bicyclol, adds 95v/v% medicinal alcohol 40ml, and mix homogeneously stirs under the condition of 80 ℃ of heating and makes dissolving;
(2) wet granulation: by the proportioning of table 4 take by weighing filler starch, Icing Sugar and be used in the disintegrating agent CMS-Na that adds, mix homogeneously adds the common molten thing that step (1) obtains, mix homogeneously adds purified water 50ml, mixing granulation again, 60 ℃ of dryings prepare the bicyclol medicine-containing particle;
(3) make preparation: in above-mentioned bicyclol medicine-containing particle, add for the disintegrating agent PVPP and the magnesium stearate lubricant that add, mix homogeneously, tabletting, specification contains bicyclol 25mg/ sheet.
Preparation method two:
1) preparation pastille mixture: by the proportioning of table 4 take by weighing active component bicyclol, filler starch and Icing Sugar and be used in the disintegrating agent CMS-Na that adds, mix homogeneously;
2) wet granulation: the proportioning by table 4 takes by weighing the solubilizing agent Tween 80, add diluent 95v/v% medicinal alcohol 40ml, mix homogeneously, stir under the condition of 80 ℃ of heating and make dissolving, join then in the pastille mixture that step 1) obtains, add purified water 50ml again, mixing granulation, 60 ℃ of dryings obtain the bicyclol medicine-containing particle;
3) make preparation: with the step (3) of preparation method one.
Embodiment 5
Component and proportioning see Table 5.
Table 5
| Component | 1000 dosage amounts (g) |
| Bicyclol | 50 |
| Solutol?H15 | 10 |
| Poloxamer | 5 |
| |
100 |
| Mannitol | 50 |
| L-HPC | 10 |
| CCMC-Na | 5 |
| Magnesium stearate | 1 |
Preparation method:
(1) preparation pastille mixture: by the proportioning of table 5 take by weighing active component bicyclol, filler lactose and mannitol and be used in the disintegrating agent L-HPC that adds, mix homogeneously;
(2) wet granulation: take by weighing solubilizing agent Solutol H15, poloxamer by proportioning, add 60v/v% medicinal alcohol 100ml, mix homogeneously, stir under the condition of 80 ℃ of heating and make dissolving, join in the pastille mixture that step (1) obtains, mixing granulation, 60 ℃ of dryings prepare the bicyclol medicine-containing particle;
(3) make preparation: in above-mentioned bicyclol medicine-containing particle, add for the disintegrating agent CCMC-Na and the magnesium stearate lubricant that add, mix homogeneously, tabletting, specification contains bicyclol 50mg/ sheet.
Embodiment 6
Component and proportioning see Table 6.
Table 6
| Component | 1000 dosage amounts (g) |
| Bicyclol | 20 |
| |
20 |
| Mannitol | 80 |
| Lactose | 40 |
| PVPP | 8 |
| Micropowder silica gel | 8 |
Preparation method:
Take by weighing by the proportioning of table 6 that all are former, adjuvant (Powdered, granularity is less than 80 mesh sieves), mix homogeneously, with whole direct powder compressions, specification contains bicyclol 20mg/ sheet, the heavy 176mg/ sheet of sheet; Or direct packaging is in hard capsule, and specification contains bicyclol 20mg/ grain.
Embodiment 7
Component and proportioning see Table 7.
Table 7
| Component | 1000 dosage amounts (g) |
| Bicyclol | 10 |
| Poloxamer | 10 |
| Cremophor?EL | 10 |
| MCC | 90 |
| CMS-Na | 2.5 |
| Micropowder silica gel | 8 |
| Magnesium stearate | 0.5 |
Preparation method one:
(1) preparation is total to molten thing: the proportioning by table 7 takes by weighing solubilizing agent poloxamer and Cremophor EL, adds the recipe quantity bicyclol, adds 95v/v% medicinal alcohol solution 30ml, and mix homogeneously stirs under the condition of 100 ℃ of heating and makes dissolving;
(2) wet granulation: the proportioning by table 7 takes by weighing filler MCC and disintegrating agent CMS-Na, mix homogeneously; Add the common molten thing that step (1) obtains, mix homogeneously; Adding concentration is that the aqueous solution 40ml of 5wt%HPMC is binding agent, mixing granulation, and 60 ℃ of dryings prepare the bicyclol medicine-containing particle;
(3) make preparation: in above-mentioned bicyclol medicine-containing particle, add magnesium stearate lubricant and fluidizer micropowder silica gel, mix homogeneously, tabletting, specification contains bicyclol 10mg/ sheet.
Preparation method two:
1) preparation pastille mixture: the proportioning by table 7 takes by weighing active component bicyclol, filler MCC and disintegrating agent CMS-Na, mix homogeneously;
2) wet granulation: the proportioning by table 7 takes by weighing solubilizing agent poloxamer and Cremophor EL, adds 95v/v% medicinal alcohol solution 40ml, and mix homogeneously stirs under the condition of 80 ℃ of heating and makes dissolving; Join in the pastille mixture that step 1) obtains, the aqueous solution 40ml that adds concentration 5wt%HPMC is binding agent, mixing granulation, and 60 ℃ of dryings prepare the bicyclol medicine-containing particle;
3) make preparation: with the step (3) of preparation method one.
Embodiment 8
Component and proportioning see Table 8.
Table 8
| Component | 1000 dosage amounts (g) |
| Bicyclol | 4 |
| Tween 80 | 20 |
| MCC? |
200 |
Preparation method one:
(1) preparation is total to molten thing: the proportioning by table 8 takes by weighing the solubilizing agent Tween 80, adds the bicyclol of recipe quantity, and the medicinal alcohol solution 50ml that adds binding agent 70v/v% dilutes, and mix homogeneously stirs under the condition of 80 ℃ of heating and makes dissolving;
(2) wet granulation: the proportioning by table 8 takes by weighing filler MCC PH101, adds the resulting molten thing altogether of step (1), mix homogeneously; The medicinal alcohol solution 40ml that adds binding agent 70v/v%, mixing granulation, 60 ℃ of dryings prepare the bicyclol medicine-containing particle;
(3) make preparation: the above-mentioned bicyclol granule that contains is sub-packed in the hard capsule, makes the bicyclol hard capsule, specification contains bicyclol 4mg/ grain.
Preparation method two:
1) preparation pastille mixture: the proportioning by table 8 takes by weighing active component bicyclol, filler MCC PH101 mix homogeneously;
2) wet granulation: the proportioning by table 1 takes by weighing the solubilizing agent Tween 80, adds 70v/v% medicinal alcohol solution 90ml, mix homogeneously, and heated and stirred makes dissolving, joins then in the pastille mixture that step 1) obtains, and mix homogeneously is granulated; 60 ℃ of dryings prepare the bicyclol medicine-containing particle;
3) make preparation: with the step (3) of preparation method one.
Embodiment 9
Component and proportioning see Table 9.
| Component | 1000 dosage amounts (g) |
| Bicyclol | 5 |
| Cremophor? |
20 |
| MCC | 90 |
| Lactose | 80 |
Preparation method one:
(1) preparation is total to molten thing: the proportioning by table 9 takes by weighing solubilizing agent Cremophor RH40, adds the bicyclol of recipe quantity, stirs under the condition of 100 ℃ of heating and makes dissolving;
(2) wet granulation: the proportioning by table 9 takes by weighing filler MCC, lactose, and mix homogeneously adds in the resulting molten thing altogether of step (1) mix homogeneously; The medicinal alcohol solution 80ml that adds binding agent 50v/v%, mixing granulation, 60 ℃ of dryings obtain the bicyclol medicine-containing particle;
(3) make preparation: the above-mentioned bicyclol granule that contains is sub-packed in the hard capsule, makes the bicyclol hard capsule, specification contains bicyclol 5mg/ grain.
Preparation method two:
1) preparation pastille mixture: the proportioning by table 8 takes by weighing active component bicyclol, filler MCC, lactose mix homogeneously;
2) wet granulation: the proportioning by table 1 takes by weighing solubilizing agent Cremophor RH40, and heated and stirred makes dissolving, joins then in the pastille mixture that step 1) obtains, and mix homogeneously adds the medicinal alcohol solution 80ml of binding agent 50v/v%, mixing granulation; 60 ℃ of dryings obtain the bicyclol medicine-containing particle;
3) make preparation: with the step (3) of preparation method one.
Embodiment 10
This enforcement uses the sample of the bicyclol conventional tablet of embodiment 2, tablet that embodiment 3 makes and listing that implementation result of the present invention is described, especially in the actual effect that improves aspect the bioavailability.
ⅰ) laboratory sample: the tablet (bicyclol 10mg sheet) of the embodiment of the invention 2 preparation, the tablet (bicyclol 15mg sheet) of the embodiment of the invention 3 preparations, the bicyclol conventional tablet (bicyclol 25mg sheet) that gone on the market.
ⅱ) experimental technique:
8 of healthy male Beagle dogs, body weight 6.0-6.8kg, fasting 20h before the experiment freely drinks water.The present invention makes two groups of intersections of tablet group administration of 10mg sheet, 15mg sheet, and middle the cleaning week (concrete mode: 3 of every dog clothes bicyclol 10mg sheets of the present invention of 1～No. 4 dog, every dog of 5～No. 8 dogs is obeyed 3 of bicyclol 15mg sheets of the present invention; Clean 3 of every dog clothes bicyclol 15mg sheets of the present invention of 1～No. 4 dog in a week back, 3 of every dog clothes bicyclol 10mg sheets of the present invention of 5～No. 8 dogs), 8 dogs of intersecting after the two weeks give the conventional tablet of listing of bicyclol 25mg sheet simultaneously.Oral each the bicyclol tablet of Beagle dog is 3 in the experiment, after the administration respectively at 5,15,30min, 1,1.5,2,3,4,6,8,12,24h veins of upper extremity get blood, blood sample is through anticoagulant heparin, centrifugal separation plasma, get 100 μ L plasma samples, behind the adding acetonitrile 200 μ L mix homogeneously, centrifugal 2 times of 14000g * 5min, get supernatant 5 μ L and carry out bicyclol content in the LC/MS/MS analysed for plasma, different preparation oral artifact availabilities are investigated in contrast.
ⅲ) experimental result:
Curve is seen Fig. 1 during conventional tablet (bicyclol 25mg sheet) the back blood plasma medicine of the tablet (bicyclol 15mg sheet) of the tablet of the oral embodiment of the invention 2 of Beagle dog (bicyclol 10mg sheet), embodiment 3 and listing.Make a concrete analysis of as follows:
1. the Beagle dog once all absorbs behind oral different bicyclol tablet 10mg, 15mg or 25mg * 3 slice very fast, curve is the multimodal phenomenon during medicine, after the administration behind the 24h blood Chinese medicine concentration still be higher than detectability, with the body giving drugs into nose of bicyclol in the past for the feature basically identical, testing result is reliable.
2. compare the Tmax(maximum plasma concentration peak time of 10mg specification bicyclol sheet with 15mg specification bicyclol sheet) shorten the Cmax(maximum plasma concentration) and AUC
0-t(area under the drug-time curve) is close with 15mg specification bicyclol sheet.
3. the AUC of 10mg specification bicyclol sheet of the present invention, 15mg specification bicyclol sheet
0-tAUC with the reference preparation 25mg specification bicyclol conventional tablet that goes on the market
0-tBasically identical.
Obviously, in the above-mentioned experiment, the embodiment of the invention 2,3 preparation specification reduce than the bicyclol conventional tablet that gone on the market, and corresponding bicyclol dosage nearly reduces half than conventional tablet, but AUC
0-tBasically identical shows that oral formulations of the present invention has than the better bioavailability of reference preparation.
Above-described embodiment just illustrates of the present invention, and the present invention also can implement with other ad hoc fashion or other particular form, and does not depart from main idea of the present invention or substitutive characteristics.Therefore, the embodiment of description all should be considered as illustrative from any aspect but not be determinate.Scope of the present invention should be by additional claim explanation, and the intention of any and claim and the variation of scope equivalence also should be within the scope of the present invention.
Claims (11)
1. bicyclol oral solid drug composition, comprise active component bicyclol and pharmaceutically acceptable auxiliaries, it is characterized in that, comprise solubilizing agent in the pharmaceutically acceptable auxiliaries, also comprise filler in the pharmaceutically acceptable auxiliaries, the weight of solubilizing agent is 0.2～5 times of bicyclol weight, and the weight of filler is 3～50 times of bicyclol weight.
2. a kind of bicyclol oral solid drug composition according to claim 1 is characterized in that, the weight of solubilizing agent is 0.3～3 times of bicyclol weight.
3. a kind of bicyclol oral solid drug composition according to claim 1 and 2, it is characterized in that solubilizing agent is selected from one or more in Polysorbate, polyoxyethylene castor oil, Polyethylene Glycol, polyoxyethylene hydroxy stearic acid ester, the polyoxyethylene polyoxypropylene block copolymer.
4. a kind of bicyclol oral solid drug composition according to claim 3 is characterized in that described Polysorbate is selected from Tween 80 and/or polysorbate60; Polyoxyethylene castor oil is the poly-hydrocarbon oxygen ester 35 of polyoxyethylene hydrogenated Oleum Ricini and/or Oleum Ricini; Polyethylene Glycol is selected from one or more among PEG200, PEG400, the PEG600; The polyoxyethylene hydroxy stearic acid ester is polyoxyethylene 12-hydroxy stearic acid ester 15; Polyoxyethylene polyoxypropylene block copolymer is poloxamer 188.
5. a kind of bicyclol oral solid drug composition according to claim 1, it is characterized in that filler is selected from one or more in microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, starch, pregelatinized Starch, dextrin, lactose, sucrose, mannitol, calcium hydrogen phosphate, the calcium sulfate.
6. a kind of bicyclol oral solid drug composition according to claim 5, it is characterized in that pharmaceutically acceptable auxiliaries also comprises disintegrating agent, binding agent, lubricant, fluidizer, suspending agent, stabilizing agent and can modify in the additive of sense organ one or more.
7. a kind of bicyclol oral solid drug composition according to claim 6, it is characterized in that described disintegrating agent is selected from one or more in carboxymethyl starch sodium, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, the low-substituted hydroxypropyl cellulose;
Described binding agent is selected from the starch slurry of alcoholic solution, the 5～10wt% of the alcoholic solution of water, suitable concentration, the water of hydroxypropyl methylcellulose that contains 3～10wt% or suitable concentration, in the gelatine size one or more;
Described lubricant or fluidizer are selected from one or more in stearate, Pulvis Talci, silicate, fumarate, Polyethylene Glycol, the grease compounds;
Described suspending agent is one or more in sodium alginate, agar, sodium carboxymethyl cellulose, the glycerol etc.;
Described stabilizing agent is antioxidant, and described antioxidant is selected from one or more in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, vitamin C, butylated hydroxyarisol, dibutyl phenol, propyl gallate, tocopherol, ascorbic acid, the cetylate.
The described additive that can modify sense organ is malic acid, fumaric acid, vanillin, Mentholum or other suitable pigments, essence.
8. the oral solid formulation that adopts the arbitrary described a kind of bicyclol oral solid drug composition of claim 1-5 to make is characterized in that described oral solid formulation is tablet, granule, capsule or packed electuary.
9. the oral solid formulation that adopts claim 6 or 7 described a kind of bicyclol oral solid drug compositions to make is characterized in that described oral solid formulation is tablet, granule, capsule or packed electuary.
10. the preparation method of the described oral solid formulation of claim 8 is selected from one of following method:
Wet granulation, method one: bicyclol and solubilizing agent be molten addition method altogether, is applicable to liquid state or semisolid solubilizing agent, may further comprise the steps:
(1) preparation is total to molten thing: take by weighing solubilizing agent and bicyclol by proportioning, mix homogeneously makes dissolving under the condition that is no more than 100 ℃ of heating;
(2) wet granulation: take by weighing filler by proportioning, add the common molten thing that step (1) obtains, mix homogeneously is granulated drying;
(3) make preparation: the particulate matter tabletting that step (2) is obtained or direct packaging obtain being suitable for oral preparation in hard capsule, packaging bag;
Wet granulation, method two: the independent addition method of solubilizing agent, be applicable to liquid state or semisolid solubilizing agent, may further comprise the steps:
1) preparation pastille mixture: take by weighing bicyclol and filler, mix homogeneously by proportioning;
2) wet granulation: take by weighing solubilizing agent by proportioning, join in the pastille mixture that step 1) obtains, mix homogeneously is granulated drying;
3) make preparation: with step 2) the particulate matter tabletting that obtains or direct packaging in hard capsule, packaging bag, obtain being suitable for oral preparation;
Full pressed powder or packing, method three: be applicable to the solubilizing agent of solid state powder shape, may further comprise the steps:
Take by weighing bicyclol and all adjuvants by proportioning, mix homogeneously, direct compression or direct packaging obtain being suitable for oral preparation in hard capsule, packaging bag.
11. the preparation method of the described oral solid formulation of claim 9 is selected from one of following method:
Wet granulation, method one: bicyclol and solubilizing agent be molten addition method altogether, is applicable to liquid state or semisolid solubilizing agent, may further comprise the steps:
(1) preparation is total to molten thing: take by weighing solubilizing agent and bicyclol by proportioning, mix homogeneously makes dissolving under the condition that is no more than 100 ℃ of heating;
(2) wet granulation: take by weighing the disintegrating agent that adds in partly or entirely being used for of filler and survival dose and other adjuvants except binding agent, lubricants of survival dose by proportioning, mix homogeneously, add the common molten thing that step (1) obtains, mix homogeneously, the binding agent that adds survival dose again, mix homogeneously is granulated drying;
(3) make preparation: add the lubricants of remaining disintegrating agent and survival dose in the particulate matter that obtains to step (2), mix homogeneously, tabletting or direct packaging obtain being suitable for oral preparation in hard capsule, packaging bag;
Wet granulation, method two: the independent addition method of solubilizing agent, be applicable to liquid state or semisolid solubilizing agent, may further comprise the steps:
1) preparation pastille mixture: take by weighing the disintegrating agent that adds in partly or entirely being used for of bicyclol, filler and survival dose and other adjuvants except binding agent, lubricants of survival dose, mix homogeneously by proportioning;
2) wet granulation: take by weighing solubilizing agent by proportioning, join in the pastille mixture that step 1) obtains, mix homogeneously adds the binding agent of survival dose again, and mix homogeneously is granulated drying;
3) make preparation: to step 2) add the lubricants of remaining disintegrating agent and survival dose in the particulate matter that obtains, mix homogeneously, tabletting or direct packaging obtain being suitable for oral preparation in hard capsule, packaging bag;
Full pressed powder or packing, method three: be applicable to the solubilizing agent of solid state powder shape, may further comprise the steps:
Take by weighing bicyclol and all adjuvants by proportioning, mix homogeneously, direct compression or direct packaging obtain being suitable for oral preparation in hard capsule, packaging bag.
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| CN108853030A (en) * | 2018-09-26 | 2018-11-23 | 李敏 | A kind of pharmaceutical preparation and preparation method thereof for treating malignant tumour |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101390851B (en) * | 2008-08-06 | 2011-03-30 | 北京协和药厂 | Double-cyclitol medicine composition containing surfactant and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101390851B (en) * | 2008-08-06 | 2011-03-30 | 北京协和药厂 | Double-cyclitol medicine composition containing surfactant and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108853030A (en) * | 2018-09-26 | 2018-11-23 | 李敏 | A kind of pharmaceutical preparation and preparation method thereof for treating malignant tumour |
| CN108853030B (en) * | 2018-09-26 | 2021-10-01 | 上海朝晖药业有限公司 | Medicinal preparation for treating malignant tumor and preparation method thereof |
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Application publication date: 20131002 |