CN104840965A - Bosentan preparation and stabilizer thereof - Google Patents
Bosentan preparation and stabilizer thereof Download PDFInfo
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- CN104840965A CN104840965A CN201510222679.3A CN201510222679A CN104840965A CN 104840965 A CN104840965 A CN 104840965A CN 201510222679 A CN201510222679 A CN 201510222679A CN 104840965 A CN104840965 A CN 104840965A
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Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a combination of bosentan pharmaceutical preparations. The combination comprises bosentan, lactose monohydrate, microcrystalline cellulose KG802, lauryl sodium sulfate or tween 80. Dissolution rate of bosentan is increased, and preparation crystal form stability is improved. The combination can be prepared to be solid oral preparations like tablets, capsules and granules, and a preparation method is simple, feasible and easy in realizing industrial large-scale production.
Description
Technical field
The invention belongs to pharmaceutical field, particularly the preparation of bosentan.
Summary of the invention
Pulmonary hypertension Pulmonary Arterial Hypertension (PAH) causes pulmonary vascular bed to get involved by Different types of etiopathogenises and pulmonary vascular resistance Progressive symmetric erythrokeratodermia is increased, and finally causes a class Pathophysiology syndrome of right heart failure.Pulmonary hypertension is divided into idiopathic PAH, familial PAH and other correlative factor PAH, comprises congenital heart disease, connective tissue disease (scleroderma etc.), chronic pulmonary thromboembolism, HIV, takes appetrol (anorexigen) etc.External report severe pulmonary hypertension prevalence is 30 ~ 50,/10 ten thousand
[2].Judge according to domestic literature data, pulmonary hypertension about 6.2 ~ 9.5 ten thousand people that current domestic hospitals is made a definite diagnosis every year, on average about 80,000 person/year.Before 2006,1 year, 2 years, 3 years of China's idiopathic pulmonary hypertension and 5 years survival rates are respectively 68.0%, 56.9%, 38.9% and 20.8%, similar to the survival rate of U.S. eighties in last century.The use of pulmonary artery expander treatment (targeted therapy) medicine significantly improves the clinical symptoms of patient, postpones the clinical deterioration rates time, improves the quality of living, the survival rate of China pulmonary hypertension patient has been had and significantly improves.Mean survival time after idiopathic pulmonary hypertension patient makes a definite diagnosis is only 2.8 years becomes history, is greater than 5 years, close to level of developed countries presently more than the survival of patients time of 50%.The research of current sitaxsentan sodium thing concentrates on 3 pathobiology approach: prostacyclin approach, nitric oxide pathway, Endothelin approach.
The representative drugs of Endothelin approach therapy approach is bosentan.It is the first endothelin-receptor antagonists of FDA approval, all has antagonism to ET-A, ET-B receptor; For III phase one line medication, short-term and long-term efficacy are also evident in efficacy, and one of IV phase critical treatment medicine, recommendation grade is B level.Several multicenter, random, double blind show, bosentan therapy constitutional or the relevant PAH of connective tissue disease (scleroderma), patient moving ability (6MWD) can be significantly improved, reduce pulmonary vascular resistance, improve hemodynamic and do not affect Heart Rate or overall blood pressure, reduce Borg dyspnoeie index, improvement or maintain the WHO functional classification of Most patients, thus delay the time of PAH progress, improving patients ' life quality and overall survival, is that treatment constitutional or scleroderma are correlated with the active drug of PAH.
Medicine plays curative effect, and need through processes such as release, infiltration, absorptions, any link of these processes goes wrong, and all can affect medicine optimum curative effect.Bosentan is almost insoluble in water, and dissolubility increases along with pH value and increases.FDA divides the highly dissoluble of apoplexy due to endogenous wind to be defined as " under 37 DEG C of conditions; the single maximum dose level medicine be dissolvable in water in the medium 250ml of pH1 ~ 7.5 is high solubility pharmaceuticals " to BCS, and according to bosentan single maximum dose level 125mg, need dissolve in the 291ml aqueous solution of pH value 7.5, therefore it is low-solubility.Disclosing bosentan in EMEA bosentan sheet assessment report is high osmosis medicine.In conjunction with its foregoing low-solubility, therefore this product bosentan belongs to Biopharmaceutics Classification (BCS) II class, low dissolving high osmosis medicine.For low-solubility-high osmosis medicine, stripping is the rate-limiting step of drug absorption.Therefore, the performance of stripping to drug effect of bosentan preparation is most important.
Usual affect oral solid formulation stripping because have crude drug self physicochemical property, as dissolubility, crystal formation, granularity, stability etc.; In addition, preparation prescription composition also can affect disintegrate, the stripping of solid preparation, even affects and change some character of preparation Raw medicine, as dissolubility, crystal formation, stability etc.Bosentan is low-solubility drug as previously mentioned, therefore, improve its preparation stripping and need improve its dissolubility; In addition, there are 16 kinds of crystal formations in bosentan according to the literature, crystal formation is different, natural drug dissolubility is different, stability also can there are differences, therefore, preparation Raw medicine need select a kind of crystal formation with good solubility, and keeps the stability of this crystal formation, prevent it at preparation preparation, storage, use procedure transfer crystal formation, and affect medicine dissolution, stripping and curative effect.Of the present inventionly to start with from these two aspects exactly, solve the solubility problem of bosentan, stable crystal form sex chromosome mosaicism, obtained dissolution good, the oral solid formulation that the quality index such as crystal formation, content and related substance are stable.
Summary of the invention
An object of the present invention is to provide a kind of bosentan solid preparation, and it has highly dissoluble.
For achieving the above object, technical scheme of the present invention is:
The solid preparation of bosentan, comprise principal agent bosentan and adjuvant, containing surface activity in described adjuvant, described surfactant comprises described surfactant and comprises any one or more in poloxamer F188, fatty glyceride, stearic acid, Tween 80 or sodium lauryl sulphate.Described adjuvant, except the surfactant mentioned, other the customary adjuvant be in pharmaceutics.
For oral solid preparation, especially concerning low dissolving Thief zone medication medication, stripping is the rate-limiting factor absorbed.Bosentan is insoluble drug, almost insoluble under water and mild acid conditions, and situation of dissolving is as shown in table 1.
The method improving insoluble drug often has:
(1) particle diameter of insoluble drug is reduced
According to Noyes-Whitney equation dC/dt=kDA (Cs-Ct), in this formula, dC/dt is dissolution velocity; KD is dissolution velocity constant; A is surface area; Cs is medicine saturation solubility; Ct is drug level.Known, particle diameter is less, and specific surface area (A) is larger, and the area contacted with related solution is wider, and stripping is faster.We are knowing the real situation in experiment, have selected (namely reducing the method for particle diameter) in reference patent of invention CN103768068A and solve the dissolution problem of bosentan oral formulations, obtain dissolution good, the preparation that impurity is few.But find in an experiment, its complex process, needs are pulverized or the mode process bosentan crude drug such as grinding or spraying dry, and these technique device therefors are expensive, and energy consumption is high, and operation link is severe, and dust from flying, is unfavorable for the health of environmental protection and operator.In addition, pulverizing or process of lapping are often along with passage of time there will be machine heating, the too high situation of temperature of charge, also need dissolution with solvents or suspendible bosentan raw material for spraying dry, these excessive temperatures and solvent may make bosentan crystal formation change, thus affect dissolution.When particularly adopting the A5 crystal formation of bosentan as raw material, crystal conversion can occur when temperature is more than 60 DEG C, lose the water of crystallization of this crystal formation, slice, thin piece dissolution is reduced to about 60% from 100%.
(2) solid dispersion mode is adopted
Solid dispersion (SD) refers to a kind of disperse system existed in solid form being highly dispersed in by medicine and being formed in solid carrier.Medicine particle diameter in the carrier, between 0.001 ~ 0.1 millimeter, is mainly used in the stripping accelerating and increase insoluble drug, improves its bioavailability.Early stage know the real situation experiment in, we have used for reference the method that patent CN102114005 mentions, namely the mode of solid dispersion solves the dissolution of bosentan: the compositions adopting polyethylene glycol 6000, polyvinylpyrrolidone, polyethylene glycol 6000 and polyvinylpyrrolidone is solid dispersion material, is mixed in solid dispersion material by bosentan raw material and prepares oral formulations.Experimental result shows, though it can make bosentan stripping obtain certain raising, but still undesirable, and product impurity can be caused too high, there is drug safety hidden danger.In addition, also there is the problem of some general character in solid dispersion, solid dispersion often adopts fusion method or solvent method preparation, the physical arrangement of normal change medicine, become the supersaturation solid solution of amorphous, part amorphous or medicine, to from thermodynamics, these states are all unstable, have the trend transforming drug crystallization.Because bosentan exists about 16 kinds crystal formations, probably change crystalline structure according to solid dispersions technique, affect stability of crystal form, thus affect stripping.Secondly, the easy moisture absorption of solid dispersion, easily aging, occur that hardness becomes large, crystallization or the situation such as overgrowth of crystal, drug dissolution reduction.In addition, be exactly Industrialization, large production scaleization uses solid dispersions technique not yet ripe at present, is mostly in laboratory scale phase of basic research.
(3) cyclodextrin saturation technique
Adopt beta-schardinger dextrin-to be also the conventional means improving drug-eluting, utilize hydrophobic outer hydrophilic space structure in cyclodextrin, can insoluble drug is wrapped in cavity structure, increase the dissolubility of medicine, improve stripping.The experiment of knowing the real situation in our early stage also uses the method attempt and improves bosentan drug-eluting, but the clinical regular size of bosentan is 62.5mg, 125mg, and as with cyclodextrin inclusion compound, drug loading is comparatively large, needs relatively large cyclodextrin, is generally principal agent 3-4 doubly; Secondly, cyclodextrin saturation technique adopts saturated solvent legal system standby usually, need use dissolution with solvents principal agent and cyclodextrin, then carry out enclose, and envelop rate more difficult control usually.Therefore, this technology is relative also more complicated, is not having, under straightforward procedure feasible condition, just to select this method.
The present invention does not adopt said method, but utilizes surfactant can reduce hydrophobic drug surface tension, and the method increasing wettability improves the hydrophilic ability of bosentan, increases its stripping.Contact angle large (>90 °) between hydrophobic drug surface and aqueous medium, capillary force is reverse, not easily makes aqueous medium infiltrate medicine inside, thus makes medicine be difficult to disintegrate stripping occurs.And surfactant can improve this situation, reduce the contact angle of hydrophobic drug surface and aqueous medium, thus increase the hydrophilic ability of hydrophobic drug, increase stripping.Dosage of surfactant is not The more the better, and it has barbotage usually, therefore, also should control its use amount when endo-medicine is selected, and occurs the untoward reaction such as flatulence, stomach discomfort after avoiding consumption to cross ambassador patient on medication.In addition, also can affect product preparation process for sodium lauryl sulphate consumption is excessive, we test display, when consumption is more than 2%, can affect bosentan tabletting effect, the phenomenon such as slice, thin piece there will be hardness reduction, sliver, top are split.We test display, and Surfactant SDS and Tween 80 effectively can improve the stripping of bosentan when 0.1%-2%, and do not affect the quality of the pharmaceutical preparations, and this weight range for oral use can not cause untoward reaction according to bibliographical information.
As preferred scheme, in described solid preparation, described surface activity is equivalent to the 0.5-1% of described bosentan solid preparation weight by weight percentage.
As preferred scheme, in described bosentan solid preparation, described bosentan solid preparation is tablet.
Separately, the reasonably combined use of lactose monohydrate and/or microcrystalline Cellulose KG802 in the present invention, is also conducive to the dissolution improving bosentan oral solid formulation.Lactose monohydrate has good hydrophilic ability, proves through our previous experiments, and it can disperse the electric charge of hydrophobic drug particle surface, improves the wettability of medicine, adds the stripping of medicine.Microcrystalline Cellulose KG802 is the microcrystalline Cellulose product developed on CEOULS PH manufacturing technology basis, and its compressibility is higher than microcrystalline Cellulose PH-101, and when preparing for bosentan tablet, during tabletting, hardness can improve 1.5-2.0 doubly; Secondly, abrasiveness and reactivity low, the advantages such as disintegrative is good.
So, as preferred scheme, in described solid preparation, also containing lactose monohydrate in described adjuvant.
As preferred scheme, in described solid preparation, described lactose monohydrate is equivalent to the 25-40% of described solid preparation weight by weight percentage.
As preferred scheme, in described solid preparation, also containing microcrystalline Cellulose KG802 in described adjuvant.
As preferred scheme, in described solid preparation, described microcrystalline Cellulose KG802 is equivalent to described solid preparation 5-10% by weight percentage.
Further, except described surfactant, described lactose monohydrate and described microcrystalline Cellulose KG802, it is 5-10% that other customary adjuvant accounts for described solid preparation percentage by weight.
As preferred scheme, in described solid preparation, the crystal formation of described bosentan is A5.For oral solid formulation, the crystal formation of preparation Raw medicine is also most important.When identical the but crystal form of drug molecular structure is different, likely there is different bioavailability, dissolubility, rate of dissolution, chemical physical stability, fusing point, color, filtrability, density and mobility.The physicochemical property character of these crystal formations often affects the molding preparation of preparation, quality stability and treatment effectiveness.Some polymorph is difficult to make preparation due to shape or hygroscopicity.Such as: acicular crystal because being with a lot of electrostatic, thus seems very sticky, and preparations shaping is comparatively difficult.Crystal formation different pharmaceutical dissolubility, bioavailability are different, so need the strict crystal formation controlling preparation Raw medicine, make it stablize, thus better play curative effect.The late nineteen eighties in last century, cause its dissolubility and bioavailability all poor to such an extent as to because of after inefficacy causes the accident than the former medicine that grinds because imitation medicine crystal form is different, U.S. FDA is very strict for the form of medicament active composition, shape, size distribution requirements.
The oriented trend changed compared with stable crystalline forms of unstable crystal form in polymorph in pharmaceuticals, the degree of transformation may be whole transformation, also may be portions turn.Be change another kind comparatively stable crystalline forms into, still change several metastable crystal form into, depend on this compound essential attribute and external condition completely.Described external condition comprises solvent, temperature, humidity, light etc.For preparation, except containing except raw material, remain at more adjuvant, often kind of adjunct ingredient complexity, some adjuvant absorbability is comparatively strong or self water content is higher, and the stability of these adjuvants to preparation of Chinese medicine crystal formation has larger influence.Therefore, in the prescription and craft screening of preparation, need using stability of crystal form as an important inspection target, to ensure the formulation products stable crystal form obtained, steady quality, stable curative effect.
Bosentan is polymorph medicine, about there are 16 kinds of crystal formations, often kind of its appearance character of crystal formation (crystal shape), dissolubility, stability are different, as the bosentan crystal formation I of patent US6136971 report, for acicular crystal, its compressibility and mobility poor, this is an extremely disadvantageous factor to the tabletting of preparation.The crystal form A 1 disclosed in patent US2011014291, A2, A4 and amorphous; The A5 crystal formation of patent US20110021547 report, the crystal form A in patent US2011015394, B, C; Crystal formation 1,2,3,4 in patent WO2008135795.Research shows that these crystal formations are all unstable, easily changes.The bosentan that I takes charge of production is A5 crystal formation, and its crystal formation is characterized as: X-ray:7.175,8.310,9.241,13.187,18.617,20.261,21.320.Crystal form A 5 has unstability, and initially preparing in tablet process, employing starch is filler, and result slice, thin piece is being subject to high temperature more than 60 DEG C, and 1 hour, crystal formation changed, and material color changes yellow into by off-white color, and crystal conversion is B2.In order to ensure the stability of A5 crystal formation in preparation, we have employed the crystal stabilization that lactose monohydrate is this product, there are in lactose monohydrate molecular structure (see following formula) 8 hydroxyls, hydrogen bond can be formed with bosentan A5 crystal formation (structural formula is shown in following formula), thus make its stable crystal form, do not turn brilliant.Composite preparation product is under influence factor's condition, high temperature 10 days (60 DEG C), high humiditys 10 days (RH92.5%), illumination 10 days (4500lx), separately acceleration (40 DEG C, RH75%) under condition in June, crystal formation is still stablized, unchanged (concrete data are in table 3).In the present invention, compositions effectively ensure that the stability of bosentan raw material A 5 crystal formation, thus ensure that constant product quality, Stability.Though only list in the present invention in compositions, lactose monohydrate is to the stability action of crystal form A 5, and analyzing it theoretically also should have similar Stabilization to other crystal formations.
As preferential scheme, in described solid preparation, the particle diameter of described bosentan is 15-100 μm.In the present invention, preparation dissolution is less demanding to crude drug particle diameter, only needs conventional particle size, the shortcoming that when can effectively avoid crude drug particle diameter excessive, medicine goes out compared with indissoluble.
In the present invention, even if raw material particle size reaches 100 μm, it also can 100% stripping.Advantage prepared by the preparation of the present composition and dissolution situation sees the following form 2.
Two of object of the present invention is to provide a kind of compositions, prepares solid preparation by described compositions, has high-dissolution and high stability.
For achieving the above object, technical scheme of the present invention is:
Compositions containing bosentan, composed of the following components by weight:
Bosentan 625-1250 part, lactose monohydrate 250-400 part, microcrystalline Cellulose KG80250-100 part, sodium lauryl sulphate sodium/Tween 80 1-20 part, added Starch Sodium 40-160 part, polyvidone k3020-40 part, silica 1 5-30 part, magnesium stearate 5-10 part.
Three of object of the present invention is the preparation method providing solid preparation, and it is applicable to suitability for industrialized production.
For achieving the above object, technical scheme of the present invention is:
Such as, by the bosentan of proper proportion, lactose monohydrate, microcrystalline Cellulose KG802, disintegrating agent and surfactant mix homogeneously, add binder solution, shear granulation, drying, granulate, dry granule add lubricant mixing, tabletting or encapsulated.
For another, by the bosentan of proper proportion, lactose monohydrate, microcrystalline Cellulose KG802, disintegrating agent mix homogeneously, add the binder solution containing surfactant, shear granulation, drying, granulate, dry granule add lubricant mixing, tabletting or encapsulated.
For another example: based on the method preparing solid preparation of above-mentioned compositions, specifically comprise the following steps:
A batch mixing
By other solid constituent mix homogeneously except silicon dioxide, magnesium stearate, obtain mixture A, fully stir in the liquid component in power 11 and suitable quantity of water medium, obtain solvent;
B prepares soft material
Steps A gained mixture A is placed in efficient wet granulator, and slowly adds described solvent, mix homogeneously, soft material processed;
C is dry
Step B gained soft material is dry under 35 DEG C ~ 40 DEG C conditions, and obtain granule, described particle drying is weightless for being not more than 6%;
D tabletting
After step C gained granule is carried out granulate, add the described silicon dioxide of formula ratio and the mixing of described magnesium stearate, tabletting, obtains tablet, wherein, is namely the preparation that the disappearance of step D does not affect other solid preparations yet.
Further, described preparation method, in described step B, after gained mixture A is placed in efficient wet granulator, slowly adds described solvent under stirring at low speed, and low stirring lowly cuts 30s ± 10s, the higher height that stirs cuts 30s ± 10s soft material, stirring at low speed discharging.
Four of object of the present invention is the stabilizing agent providing bosentan crystal formation, and it can reduce the generation of bosentan crystal conversion.
For achieving the above object, technical scheme of the present invention is:
A stabilizing agent for bosentan crystal formation, described stabilizing agent is lactose monohydrate.As preferred scheme, the crystal formation of described bosentan is A5 type.
Five of object of the present invention is to provide the solid preparation containing bosentan A5 crystal formation, its stable in properties, crystal formation not easily occurs and makes the transition.
For achieving the above object, technical scheme of the present invention is:
Solid preparation containing bosentan A5 crystal formation, containing lactose monohydrate in the adjuvant in described solid preparation.
As preferred scheme, in described solid preparation, described lactose monohydrate accounts for the 25-40% of described solid preparation by weight percentage.
Six of object of the present invention is to give security a kind of method of bosentan stable crystal form, and the method is for ensureing that bosentan preparation stabilization provides thinking.
For achieving the above object, technical scheme of the present invention is:
Make bosentan A5 crystal formation not change a method for crystal formation, use lactose monohydrate as stabilizing agent.
Beneficial effect of the present invention:
1) bosentan compositions of the present invention, efficiently solves slightly solubility bosentan medicine and makes the low difficult problem of oral formulations dissolution, effectively ensure that biological utilisation and the therapeutic effect of bosentan.Note: the present invention is less demanding to crude drug particle diameter, only needs conventional particle size, can effectively avoid because crude drug particle diameter is excessive or the too small preparation drawback caused.
2) bosentan compositions of the present invention, efficiently solve bosentan polymorph in pharmaceuticals unstability, crystal formation turns problem mutually, has obtained the oral solid formulation of stable crystal form, effectively ensure that biological utilisation and the therapeutic effect of bosentan.Note: the present composition is under influence factor's condition, high temperature 10 days (60 DEG C), high humiditys 10 days (RH92.5%), illumination 10 days (4500lx), separately acceleration (40 DEG C, RH75%), under condition in June, crystal formation is still stablized.
3) bosentan composite preparation of the present invention, product content, related substance are stablized, and effectively ensure that safety and the curative effect of bosentan.Note: the present composition accelerates content and related substance quite stable in June through (40 DEG C, RH75%), with 0 day than without any change.
4) present composition uses simple preparation technology to accomplish scale production, and improves the method for pharmaceutical preparation dissolution, greatly saved energy consumption and cost relative to other.
5) present composition produces obtained product, has broken the monopolization of imported product, has obtained the domestic bosentan oral solid formulation that price is relatively cheap, really achieve super quality and competitive price, for patients with pulmonary hypertension significantly reduces financial burden.
In prior art, patent CN101175484 discloses a kind of bosentan dispersible tablet, becomes to contain the suspension of fine particle so that children by dispersion disintegrate.Its goal of the invention is only and provides a kind of and be convenient to child's bosentan oral tablet used, do not consider or fundamentally do not solve the problem of bosentan low-solubility, although solve the very fast disintegrate scattering problem of slice, thin piece, but those skilled in the art are known, tablet disintegrates disperses, do not represent medicine one effectively stripping surely, in this invention, 15min also only has 70% medicine dissolution, thus affects onset time and the effect of medicine.
Patent CN1001162A discloses the compositions comprising bosentan, filler, binding agent, disintegrating agent, and adopts wet granulation mode to obtain wet granular, dry, add lubricant after encapsulated.This method adopts add mode in powder because of binding agent, obtains granule really up to the mark, affects bosentan stripping, reduce its bioavailability.
Patent CN102114005 discloses a kind of Tracleer capsule and preparation method thereof, this capsule is containing bosentan crude drug, solid dispersion, filler, disintegrating agent, binding agent and lubricant, and wherein solid dispersion adopts the compositions of polyethylene glycol 6000, polyvinylpyrrolidone, polyethylene glycol 6000 and polyvinylpyrrolidone.Solid dispersion is also improve dissolution common method, but it exists the problem of some general character, and solid dispersion is easily aging, and long storage periods can affect the homogeneity of stripping, even can hinder stripping; Another problem is exactly Industrialization, and large production scaleization uses solid dispersions technique not yet ripe at present, is mostly in the laboratory research stage.In addition, although the dissolution that improve Tracleer capsule should be invented, but still undesirable, and cause product impurity too high, there is drug safety hidden danger.
Patent CN103768068A discloses a kind of bosentan compositions, and it comprises bosentan, diluent, disintegrating agent and binding agent, not containing solid dispersion.This invention is also be conceived to improve bosentan stripping, adopts to control bosentan crude drug particle diameter and reach increase-volume object, the particle diameter as controlled active component bosentan in invention little to D (0.9) be less than 80 μm, preferred 10-50 μm.Particle diameter is less, and specific surface area is larger, contacts wide, effectively can increase the dissolution of medicine with solution (comprising dissolution medium, gastric solubleness liquid etc.).But just as described in that patent, particle diameter can not be too small, not so can increase complicated process of preparation, as disintegrating process difficulty increases, to again lower than less than 5 μm, comminution by gas stream or ball mill is adopted also to be difficult to reach this Particle size requirements.In addition, raw material is thinner, quality is lighter, and mobility is poorer, needs binding agent more, has a strong impact on the complexity of preparation and tablet forming technique.In addition; this invention is not considered that raw material is pulverized again, is ground, whether can affect the transformation of bosentan crystal formation in spray-drying process; pulverizing, grinding, spraying dry are usually along with high temperature, stronger shearing force or frictional force; or spraying solvent, this type of factor can accelerate the unstability of raw material crystal formation usually.Although this invention improves the dissolution of formulation products by the particle diameter controlling raw material, preparation process adds operation, as pulverizing, grinding or spraying dry etc., adds the adverse effect that these techniques are brought to crude drug stability of crystal form simultaneously.This patent whole preparation technology relative complex, cost and energy consumption are relatively high.
At present, domestic bosentan preparation is the bosentan sheet of Actelion company of import Switzerland, expensive, retail price 19980 yuan/box, and monthly medical expense is up to 21407 yuan, and Most patients is difficult to bear.According to another bibliographical information, the bioavailability of oral tablet only has about 50%.Therefore, be necessary that development & production goes out a kind of high stripping, high-selenium corn, high bioavailability, the quality index such as content, impurity, crystal formation have good stability, the domestic bosentan oral solid formulation of affordable, and the real super quality and competitive price that realize are to alleviate patient economy burden.
In order to overcome above-mentioned technological deficiency and process complexity, the adjuvants such as bosentan and surfactant, hydrophilic lactose monohydrate, microcrystalline Cellulose KG802 are formed compositions by us, can reduce by surfactant the hydrophilic ability that capillary effect enhances hydrophobic drug bosentan, add the dissolution of bosentan.Secondly, the utilization of hydrophilicity condiment lactose proper proportion is also conducive to the stripping of bosentan.In addition, the ability that the present invention utilizes lactose monohydrate and bosentan to form hydrogen bond solves bosentan polymorphic change problem.By the oral solid formulation that the present composition is obtained, its dissolution is good, and stable crystal form, the quality index such as content, related substance is all good.Present invention process is simple, and normal wet granulating process just can realize, and eliminates and beats powder or grinding or drying process with atomizing, saved cost and energy consumption, shown that present invention process is reasonable, feasible, and have repeatability through large production checking.The present invention can provide a kind of bosentan oral solid formulation of super quality and competitive price for vast patients with pulmonary hypertension.
Accompanying drawing explanation
Fig. 1 is conventional bosentan compositions (Comparative Examples A)-0 day, and the crystal formation that raw material particle size is 15 μm differentiates figure.
Fig. 2 is conventional bosentan compositions-40 DEG C, and RH75% accelerates June, and the crystal formation that raw material particle size is 15 μm differentiates figure.
Fig. 3 is conventional bosentan compositions-0 day, and the crystal formation that raw material particle size is 100 μm differentiates figure.
Fig. 4 is conventional bosentan compositions-40 DEG C, and RH75% accelerates June, and the crystal formation that raw material particle size is 100 μm differentiates figure.
Fig. 5 is that the embodiment of the present invention crystal formation of 1-0 day differentiates figure.
Fig. 6 is that the embodiment of the present invention 1-high temperature 60 DEG C of crystal formations of 10 days differentiate figure.
Fig. 7 is that the embodiment of the present invention 1-high humidity crystal formation of RH92.5%10 days differentiates figure.
Fig. 8 is that the embodiment of the present invention 1-illumination crystal formation of 4500lx10 days differentiates figure.
Fig. 9 is the embodiment of the present invention 1-40 DEG C, and the crystal formation that RH75% accelerates June differentiates figure.
Figure 10 is that the embodiment of the present invention 2-0 day-crystal formation differentiates figure.
Figure 11 is the embodiment of the present invention 2-40 DEG C, and the crystal formation that RH75% accelerates June differentiates figure.
Figure 12 is that the embodiment of the present invention crystal formation of 3-0 day differentiates figure.
Figure 13 is the embodiment of the present invention 3-40 DEG C, and the crystal formation that RH75% accelerates June differentiates figure.
Figure 14 is that the embodiment of the present invention crystal formation of 4-0 day differentiates figure.
Figure 15 is the embodiment of the present invention 4-40 DEG C, and the crystal formation that RH75% accelerates June differentiates figure.
Detailed description of the invention
Illustrated embodiment is to be described content of the present invention better, but is not that content of the present invention is only limitted to illustrated embodiment.So those of ordinary skill in the art carry out nonessential improvement and adjustment according to foregoing invention content to embodiment, still belong to protection scope of the present invention.Embodiment bosentan used is A5 crystal formation.
Prepared by Part I
Embodiment 1
1 preparation prescription: (making 10000 altogether)
2 preparation technologies
1) recipe quantity bosentan, lactose monohydrate, microcrystalline Cellulose KG802, carboxymethylstach sodium and sodium lauryl sulphate sodium sulfate are mixed, for subsequent use;
2) recipe quantity PVP K30 is dissolved in purified water, stirs clearly molten, for subsequent use.
3) by 1) in mixed powder be placed in efficient wet granulator, slowly add the PVP K30 aqueous solution of recipe quantity under stirring at low speed, low stirring lowly cuts 30s, the higher height that stirs cuts 30s soft material, stirring at low speed discharging.
4) wet granular is placed in boiling drier, opens blower fan, regulate temperature of charge to be 35 DEG C ~ 40 DEG C, after dry 10 ~ 15min, discharging, controls particle drying weightless for being not more than 6%.
5) dry granule is with after 20 mesh sieve granulate, adds the silicon dioxide of recipe quantity, magnesium stearate mixing;
6) by middle product cubage sheet weight, tabletting, gets product.
Embodiment 2
1 preparation prescription: (making 10000 altogether)
2 preparation technologies
1) recipe quantity bosentan, lactose monohydrate, microcrystalline Cellulose KG802, carboxymethylstach sodium and sodium lauryl sulphate sodium sulfate are mixed, for subsequent use;
2) recipe quantity PVP K30 is dissolved in purified water, stirs clearly molten, for subsequent use.
3) by 1) in mixed powder be placed in efficient wet granulator, slowly add the PVP K30 aqueous solution of recipe quantity under stirring at low speed, low stirring lowly cuts 30s, the higher height that stirs cuts 30s soft material, stirring at low speed discharging.
4) wet granular is placed in boiling drier, opens blower fan, regulate temperature of charge to be 35 DEG C ~ 40 DEG C, after dry 10 ~ 15min, discharging, controls particle drying weightless for being not more than 6%.
5) dry granule is with after 20 mesh sieve granulate, adds the silicon dioxide of recipe quantity, magnesium stearate mixing;
6) by middle product cubage sheet weight, tabletting, gets product.
Embodiment 3
1 preparation prescription: (making 10000 altogether)
2 preparation technologies
1) by recipe quantity bosentan, lactose monohydrate, microcrystalline Cellulose KG802, carboxymethylstach sodium mixing, for subsequent use;
2) recipe quantity PVP K30, Tween 80 are dissolved in purified water, stir clearly molten, for subsequent use.
3) by 1) in mixed powder be placed in efficient wet granulator, slowly add the PVP K30 aqueous solution of recipe quantity under stirring at low speed, low stirring lowly cuts 30s, the higher height that stirs cuts 30s soft material, stirring at low speed discharging.
4) wet granular is placed in boiling drier, opens blower fan, regulate temperature of charge to be 35 DEG C ~ 40 DEG C, after dry 10 ~ 15min, discharging, controls particle drying weightless for being not more than 6%.
5) dry granule is with after 20 mesh sieve granulate, adds the silicon dioxide of recipe quantity, magnesium stearate mixing;
6) by middle product cubage sheet weight, tabletting, gets product.
Embodiment 4
1 preparation prescription: (making 10000 altogether)
2 preparation technologies
1) by recipe quantity bosentan, lactose monohydrate, microcrystalline Cellulose KG802, carboxymethylstach sodium mixing, for subsequent use;
2) recipe quantity PVP K30, Tween 80 are dissolved in purified water, stir clearly molten, for subsequent use.
3) by 1) in mixed powder be placed in efficient wet granulator, slowly add the PVP K30 aqueous solution of recipe quantity under stirring at low speed, low stirring lowly cuts 30s, the higher height that stirs cuts 30s soft material, stirring at low speed discharging.
4) wet granular is placed in boiling drier, opens blower fan, regulate temperature of charge to be 35 DEG C ~ 40 DEG C, after dry 10 ~ 15min, discharging, controls particle drying weightless for being not more than 6%.
5) dry granule is with after 20 mesh sieve granulate, adds the silicon dioxide of recipe quantity, magnesium stearate mixing;
6) by middle product cubage sheet weight, tabletting, gets product.
Comparative Examples A
Conventional bosentan preparation method of composition is as follows:
Bosentan raw material particle size is 15 μm
1 preparation prescription: (making 10000 altogether)
2 preparation technologies
1) recipe quantity bosentan, starch and carboxymethylstach sodium are mixed, for subsequent use;
2) recipe quantity PVP K30 is dissolved in purified water, stirs clearly molten, for subsequent use.
3) by 1) in mixed powder be placed in efficient wet granulator, slowly add the PVP K30 aqueous solution of recipe quantity under stirring at low speed, low stirring lowly cuts 30s, the higher height that stirs cuts 30s soft material, stirring at low speed discharging.
4) wet granular is placed in boiling drier, opens blower fan, regulate temperature of charge to be 35 DEG C ~ 40 DEG C, after dry 10 ~ 15min, discharging, controls particle drying weightless for being not more than 6%.
5) dry granule is with after 20 mesh sieve granulate, adds the silicon dioxide of recipe quantity, magnesium stearate mixing;
6) by middle product cubage sheet weight, tabletting, gets product.
Comparative example B
Bosentan raw material particle size is 100 μm
1 preparation prescription: (making 10000 altogether)
2 preparation technologies
1) recipe quantity bosentan, starch and carboxymethylstach sodium are mixed, for subsequent use;
2) recipe quantity PVP K30 is dissolved in purified water, stirs clearly molten, for subsequent use.
3) by 1) in mixed powder be placed in efficient wet granulator, slowly add the PVP K30 aqueous solution of recipe quantity under stirring at low speed, low stirring lowly cuts 30s, the higher height that stirs cuts 30s soft material, stirring at low speed discharging.
4) wet granular is placed in boiling drier, opens blower fan, regulate temperature of charge to be 35 DEG C ~ 40 DEG C, after dry 10 ~ 15min, discharging, controls particle drying weightless for being not more than 6%.
5) dry granule is with after 20 mesh sieve granulate, adds the silicon dioxide of recipe quantity, magnesium stearate mixing;
6) by middle product cubage sheet weight, tabletting, gets product.
Part II is investigated
Method:
A deliquescent assay method:
Get bosentan raw material appropriate, add a certain amount of solvent, under 25 DEG C ± 2 DEG C conditions every 5 minutes powerful jolting 30 second, within 30 minutes, observe dissolving situation, during as cannot see particles of solute or drop, namely thinking and dissolving completely.By Chinese Pharmacopoeia version note on the use solubility test law regulation in 2010, solute dissolves completely, is namely called the dissolubility of this test sample.
B dissolution determination method:
Get bosentan sheet appropriate, according to dissolution method (Chinese Pharmacopoeia version annex Ⅹ C second method in 2010), with 900ml purified water for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, when 30min, get solution appropriate, filter, it is appropriate that precision measures subsequent filtrate, add stripping medium and make the solution about containing anhydrous bosentan 14 μ g in every 1ml, according to spectrophotography (Chinese Pharmacopoeia version annex IV A in 2010), measure absorbance at the wavelength place of 272nm.Separately get bosentan reference substance and be about 15mg, accurately weighed, put in 100ml measuring bottle, add acetonitrile 10ml and make dissolving, add stripping medium to scale, shake up, precision measures 5ml, put in 50ml measuring bottle, add stripping medium to scale, shake up, in contrast product solution, be measured in the same method absorbance, calculate the dissolution of every sheet.
C crystal formation assay method:
Get this product fine powder appropriate (being about equivalent to bosentan 1g), add water appropriate, stir, filter, filtering residue is rinsed again by suitable quantity of water, residue is placed in 60 DEG C of vacuum dryings 2 hours, gets dried residue and measure according to x-ray powder diffraction (Chinese Pharmacopoeia version in 2010 two annex Ⅸ F).Should be A5 crystal formation (peak of 7.15,8.31,9.26,13.19,18.63,20.28,21.52 ± 0.2 should be had).
D content assaying method:
Adopt and measure according to high performance liquid chromatography (Chinese Pharmacopoeia version annex V D in 2010).
Chromatographic condition and system suitability are filler (250mm × 4.6mm 5 μm) with eight alkyl silane bonded silica gels; Be mobile phase with acetonitrile-liquor sodii citratis (get Citric Acid Monohydrate 7.36g, the 1000ml that adds water makes dissolving, regulates pH to 4.5 ± 0.1 with saturated sodium hydroxide solution) (60:50); Determined wavelength is 272nm.Theoretical cam curve calculates should be not less than 2000 by bosentan peak.
Algoscopy gets this product 20, accurately weighed, porphyrize, and precision takes in right amount (being about equivalent to anhydrous bosentan 25mg), put in 100ml measuring bottle, add acetonitrile 10ml, the ultrasonic bosentan that makes dissolves, and is diluted to scale with diluent, shake up, filter, get subsequent filtrate as need testing solution.Separately get bosentan reference substance and be about 25mg (in anhydride), accurately weighed, put in 100ml measuring bottle, add that acetonitrile 10ml is ultrasonic makes dissolving, add diluent and be diluted to scale, shake up, in contrast product solution.Accurate amount reference substance solution and each 20 μ l of need testing solution, respectively injection liquid chromatography, record chromatogram.By external standard method with calculated by peak area, to obtain final product.
E determination of related substances method:
Precision measures the reference substance solution 1ml under assay item, is placed in 100ml measuring bottle, adds diluent and is diluted to scale, shake up, in contrast solution.Precision takes bosentan respectively, A, B, C reference substance is in right amount each, adds acetonitrile and dissolves and dilute the mixed solution made all about containing 100 μ g in every 1ml; Precision measures in right amount, adds diluent dilution and makes the mixed solution all about containing 10 μ g in every 1ml, as system suitability solution.According to the chromatographic condition under assay item, measure system suitability solution 20 μ l injection liquid chromatography, record chromatogram; A, bosentan, B, C is followed successively by by peak sequence; Regulate detection sensitivity, make the peak height at C peak be about 80% of full scale; The separating degree at A peak and bosentan peak should conform with the regulations.The accurate each 20 μ l of need testing solution measured under contrast solution and assay item again, injection liquid chromatography respectively, record chromatogram is to 5 times of main peak retention time.If any impurity peaks (except solvent peak) in the chromatogram of need testing solution, the calibration peak area (peak area of A is multiplied by correction factor 1.34) of A must not be greater than 0.2 times (0.2%) of contrast solution main peak peak area, the peak area of B must not be greater than 0.2 times (0.2%) of contrast solution main peak peak area, the calibration peak area (peak area of C is multiplied by correction factor 1.21) of C must not be greater than 0.2 times (0.2%) of contrast solution main peak peak area, the peak area of other single impurity must not be greater than 0.2 times (0.2%) of contrast solution main peak peak area, other impurity peak area and 0.4 times (0.4%) of contrast solution main peak peak area must not be greater than.In need testing solution chromatogram, can ignore in any peak being less than contrast solution main peak area 0.05 times.
Table 1 crude drug dissolves situation in different pH value aqueous solution
Table 2 present composition formulation process and preparation dissolution situation
Table 3 present composition stable crystal form implementations
Table 4 present composition content and related substance steadiness
What finally illustrate is, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to technical scheme of the present invention or equivalent replacement, and not departing from aim and the scope of technical solution of the present invention, it all should be encompassed in the middle of right of the present invention.
Claims (8)
1. a stabilizing agent for bosentan A5 crystal formation, is characterized in that, described stabilizing agent is lactose monohydrate.
2. the solid preparation containing bosentan A5 crystal formation, is characterized in that, containing lactose monohydrate in the adjuvant in described solid preparation.
3. solid preparation according to claim 16, is characterized in that, described lactose monohydrate accounts for the 25-40% of described solid preparation by weight percentage.
4. make bosentan A5 crystal formation not change a method for crystal formation, it is characterized in that, use lactose monohydrate as stabilizing agent.
5. solid preparation according to claim 2, is characterized in that, also containing microcrystalline Cellulose KG802 in described adjuvant.
6. solid preparation according to claim 5, is characterized in that, described microcrystalline Cellulose KG802 is equivalent to described solid preparation 5-10% by weight percentage.
7. solid preparation according to claim 6, is characterized in that, in described adjuvant, except surfactant, described lactose monohydrate and described microcrystalline Cellulose KG802, it is 5-10% that other customary adjuvant accounts for described solid preparation percentage by weight.
8. solid preparation according to claim 2, is characterized in that, the particle diameter of described bosentan is 15-100 μm.
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| WO2013098577A1 (en) * | 2011-12-31 | 2013-07-04 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Pharmaceutical compositions of bosentan |
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