CN103211815A - Valsartan amlodipine tablet composition and preparation method - Google Patents
Valsartan amlodipine tablet composition and preparation method Download PDFInfo
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Abstract
The invention relates to a valsartan amlodipine tablet composition and a preparation method, an active component of the valsartan amlodipine tablet composition is valsartan and amlodipine besylate tablet , an auxiliary material comprises microcrystalline cellulose, croscarmellose sodium , hydroxypropyl methylcellulose, magnesium stearate and silica; the valsartan amlodipine tablet composition employs a wet method for granulation and tabletting; the preparation method has the advantages of little disintegrating agent , high dissolution rate , simple production technology and low equipment requirement; through detections, the tablet prepared by the valsartan amlodipine tablet composition and the preparation method has good dissolution performance.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, exactly relate to a kind of pharmaceutical composition that contains valsartan and Amlodipine Besylate Tablet and preparation method thereof.
Background technology
Hypertension has become the great public health difficult problem in the global range, and existing nearly 1,000,000,000 people in the whole world suffer from hypertension, calculate 2025 and will reach 1,500,000,000 people.Whole world mortality of hypertension the highest country be that the Black American is about 40%, and England, Sweden and Italy are about 38%, and Spain is about 45%, Germany the most about 55%.At present, the mortality of hypertension of China also surpasses 25%, and this rising impetus is still continuing.Statistics shows that the hypertension therapeutic rate city of China is 17.4%, and the rural area is 5.4%; Control rate through treatment only is 2.9%.Therefore, statistical data shows that China's hypertension prevalence constantly increases, but treatment rate, control rate are very low, have formed huge contrast.According to the WHO prediction, will account for 79% of China's cause of death to the year two thousand twenty expense infectious disease, wherein the cardiovascular diseases will account for the first place.In order to contain the arrival on this cardiovascular diseases peak, carry out the control of high blood pressure disease energetically, the active treatment hyperpietic, extremely urgent.
At present, can obtainable blood pressure lowering up to standard (systolic pressure＜140mmHg, the rate less than 50% of diastolic pressure＜90mmHg) needs drug combination for most of patients to the independent treatment of the antihypertensive drug of clinical use.Result of study confirms that the clinical demand of single use depressor is reducing, and drug combination treatment hypertension has become a kind of trend.The treatment of associating antihypertensive drug can obtain the blood pressure lowering amplitude similar or bigger to the single medicine doubling dosage with less respectively dosage, thereby improves the blood pressure lowering compliance rate of antihypertensive drug treatment greatly.In the clinical trial of a plurality of antihypertensive drug, to light moderate hypertension patient, the blood pressure lowering compliance rate of associating antihypertensive drug all reaches more than 70%; Even to the severe hyperpietic, also can obtain better therapeutic, the blood pressure lowering amplitude is bigger, and the controlling of blood pressure compliance rate is higher.Simultaneously, owing to use less respectively dosage and mechanism of drug action difference, the clinical adverse incidence rate reduces, and the safety and the toleration of receiving treatment for a long time significantly improve.At present, various places hypertension therapeutic guide recommends to use multiple medication combined scheme, for example, and scheme of combination drug therapy such as ACEI and diuretic, ACEI and CCB, ARB and diuretic, beta-blocker and diuretic.Existing 9 compound preparations are respectively valsartan+hydrochlorothiazide, losartan+hydrochlorothiazide, irbesartan+hydrochlorothiazide, telmisartan+hydrochlorothiazide, amlodipine+benazepril, enalapril+hydrochlorothiazide, quinapril+hydrochlorothiazide, moexipril+hydrochlorothiazide, amlodipine+atorvastatin in the last 500 medicine that is in great demand.
A kind of new compositions of up-to-date listing---ARB(angiotensin receptor blocker) with the CCB(dihydropyridine calcium channel blocker) therapeutic alliance is with the efficacy of antihypertensive treatment of its optimization and complementary noticeable at mechanism of action, can be used for preventing and treating cardiovascular system diseases such as hypertension, coronary heart disease, heart failure.The valsartan amlodipine is calcium ion channel blocker amlodipine and blood vessel and opens a plain acceptor inhibitor valsartan and combine.Valsartan and amlodipine all are the leading kinds in the field for the treatment of separately, and valsartan and amlodipine sales volume in 2007 surpass 6,000,000,000 dollars, but are in the rising stage of growing up in China.
The valsartan amlodipine medicament composition, both part by weight great disparities are very big, the consumption of valsartan is far above amlodipine, the bioavailability scope (10～30%) of absolute oral availability of valsartan lower (25%) and broad in addition, and valsartan also has the dissolubility that depends on pH, in addition, the challenge of valsartan oral formulations also is the bulk density that it is low.Amlodipine Besylate Tablet is slightly soluble in water, and absolute bioavailability is 64～90%.Because the solid orally ingestible that these complicated biopharmacy character cause developing with bioequivalent valsartan of independent assortment and Amlodipine Besylate Tablet fixed combination faces the challenge.
Given this, disclose multiple correlation technique in recent years, studied from different perspectives, to solve more existing technical problems in the valsartan amlodipine medicament composition preparation process.
CN101485657 and CN102091069 adopt roll-in method earlier valsartan to be prepared into compact, again with amlodipine and direct compressing dry granulation of other adjuvant and fill capsule, technical problem such as the not good and capsule content uniformity of powder fluidity is defective when solving tabletting.CN101926798 is prepared into the dispersion sheet with the valsartan amlodipine, gives quick-acting quick-dissolving characteristics, and the difficult person that is fit to swallow uses.CN101836981 adopts solid dispersion technology to prepare valsartan amlodipine compositions, can promote significantly that the stripping of medicine and medicine absorb at gastrointestinal, has overcome the defective that the external stripping of Amlodipine Besylate Tablet is poor, bioavailability is low.It is main adjuvant that CN101647797 utilizes microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate, adopts the direct compression technology under the adding proportion of optimizing, and has obtained the high-dissolution and the high stability of valsartan and amlodipine.CN101862328 utilizes microcrystalline Cellulose pH102, crospolyvinylpyrrolidone, hydroxypropyl emthylcellulose and magnesium stearate to be adjuvant, is prepared into capsule under suitable adding proportion, obtains good dissolution and stability.CN101843615 is prepared into the dispersion sheet after the granulation separately with valsartan and amlodipine, can obtain excellent drug stability, disintegrative and dissolution and high bioavailability under the formulation and technology of optimizing.Stable bad, the disintegrate and the stripping that have solved that said composition exists are slow, problems such as the low and cost height of oral administration biaavailability.CN102028686 is that disintegrating agent, microcrystalline Cellulose are that filler and silicon dioxide are lubricant with the crospovidone, and the high dose valsartan is become capsule with the amlodipine preparation of compositions, has solved by injectivity optimizing to be difficult for collapsing the problem of loosing with stripping.CN101987098 utilizes microcrystalline Cellulose 102, cross-linking sodium carboxymethyl cellulose and magnesium stearate to be adjuvant, adopt dry granulation prepared valsartan amlodipine sheet, overcome heating to the degradation problem that amlodipine causes, obtained good fluidity, good, the unconspicuous good result of tablet weight variation of dissolution.
Because the diversity of valsartan and two principal agent physicochemical properties of Amlodipine Besylate Tablet adopts routine prescription and conventional preparation technology, be difficult to solve release and the lower technical problem of bioavailability in medicine stripping, the body.According to existing adjuvant and working condition, guaranteeing to have lower production cost and simple preparation technology, under the prerequisite that adapts to large-scale industrial production, be necessary to work out a kind of suitable prescription and form and preparation technology, give good bioavailability of valsartan amlodipine and stability of drug products.
Summary of the invention
The object of the present invention is to provide a kind of new valsartan and benzenesulfonic acid amlodipine medicament composition, by the adjuvant composition of innovation and the adjuvant ratio of optimizing, success solves that mobility of particle is bad, medicine disintegrate and technical problem such as stripping is undesirable, tablet weight variation is big, bioavailability is low, and obtaining prescription does not need simply, that special process and equipment, medicine stability improve, dissolution is good, absorb the valsartan amlodipine tablet fast, that bioavailability is high.
Simultaneously, the present invention also provides the described new valsartan and the preparation method of benzenesulfonic acid amlodipine medicament composition.
Valsartan amlodipine medicament composition of the present invention is made up of valsartan and Amlodipine Besylate Tablet, disintegrating agent cross-linking sodium carboxymethyl cellulose, diluents microcrystalline cellulose, binding agent hypromellose, magnesium stearate lubricant, fluidizer silicon dioxide.
The active component of valsartan amlodipine medicament composition of the present invention is valsartan and Amlodipine Besylate Tablet, in unit of weight (part), the addition of valsartan is 80～320 weight portions, and the addition of Amlodipine Besylate Tablet is 5～10 weight portions (in amlodipines).
The disintegrating agent of valsartan amlodipine medicament composition of the present invention is a cross-linking sodium carboxymethyl cellulose, adds 80 weight portions in valsartan, and the addition of cross-linking sodium carboxymethyl cellulose is 4～15 weight portions; The diluent of valsartan amlodipine medicament composition of the present invention is a microcrystalline Cellulose, adds 80 weight portions in valsartan, and the addition of microcrystalline Cellulose is 50～75 weight portions; The binding agent of valsartan amlodipine medicament composition of the present invention is a hypromellose, adds 80 weight portions in valsartan, and the addition of hypromellose is 1.5～3 weight portions; The lubricant of valsartan amlodipine medicament composition of the present invention is a magnesium stearate, adds 80 weight portions in valsartan, and the addition of magnesium stearate is 0.5～1.5 weight portion; The fluidizer of valsartan amlodipine medicament composition of the present invention is a silicon dioxide, adds 80 weight portions in valsartan, and the addition of silicon dioxide is 1～2 weight portion.
Valsartan amlodipine medicament composition of the present invention, hypromellose wherein is preferably hypromellose E15.
Valsartan amlodipine medicament composition of the present invention, its preparation method comprises:
1) valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose are sieved respectively, standby;
2) with purified water hypromellose is mixed with solution, standby;
3) take by weighing above-mentioned standby valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose and partial cross-linked sodium carboxymethyl cellulose according to recipe quantity, mix homogeneously adds standby hypromellose solution then, mixes, until forming single-size, obtain wet granular;
4) with wet grain drying, obtain dried granule, dried granule granulate, standby;
5) with magnesium stearate, silicon dioxide and residue cross-linking sodium carboxymethyl cellulose and dried granule mix homogeneously, obtain pharmaceutical composition;
6) resulting pharmaceutical composition is carried out direct pressed powder, coating, obtain described Film coated tablets.
Valsartan amlodipine medicament composition of the present invention, sieving described in the step 1) of its preparation method to crossing 80～100 mesh sieves; Step 2) the hypromellose solution described in is 2～5% hypromellose aqueous solution; The amount of the partial cross-linked sodium carboxymethyl cellulose described in the step 3) is 1/2nd of a recipe quantity.
Valsartan amlodipine medicament composition of the present invention, the drying described in the step 4) of its preparation method are under 50～80 ℃ of conditions dry 1～4 hour; Described dried particulate moisture is below 3%; Described granulate is that dried granule is crossed 20～40 mesh sieves.
Valsartan amlodipine medicament composition of the present invention, the step 3) of its preparation method and 5) mix homogeneously described in adopts the equivalent method of progressively increasing to carry out.
Valsartan amlodipine medicament composition of the present invention, the tabletting described in the step 6) of its preparation method are at 5～8kg with the slice, thin piece Hardness Control; Described coating is that the coating solution that adopts Opadry 03B68903 and purified water to form carries out coating.
Among the present invention, the content uniformity of the flowability of powder body, Amlodipine Besylate Tablet and color and luster are all closely related with property in the tablet forming technique of valsartan amlodipine medicament composition and the preparation process.At present, tablet producing technology can be divided into wet granule compression tablet technology, dry granulation tablet forming technique and technique of direct powder compression.Wet granule compression tablet technology is domestic the most frequently used tablet producing technology, add binding agent in the prescription, can promote the compressibility and the cohesive of powder,, poor compressibility poor for flowability, the medicine that dosage is big can obtain the powder suitable flowability properties by wet granulation; For the little medicine of dosage can by wet granulation reach content accurately, good dispersion and the uniform requirement of color and luster.Technique of direct powder compression and dry granulation tablet forming technique be mainly used in to wet, thermo-responsive be medicine, wherein the dry granulation tablet forming technique is to the having relatively high expectations of equipment and adjuvant, domestic application is less; Technique of direct powder compression requires principal agent better mobile, or the proportion of principal agent in prescription lower (the general requirement is lower than 30%).Simultaneously, technique of direct powder compression also has higher technology and investment requirement to adjuvant, equipment, technology etc.As, adjuvant must have good flowability, compressibility and lubricity, also needs suitable bulk density and bigger medicine saturation.Tablet machine must be equipped with vibration and raise powder or the powder device is raised in pressure, to solve the bigger problem of tablet weight variation; Must be equipped with prepressing device, to overcome the problem that technique of direct powder compression is easy to generate sliver; Must be equipped with tight combination the between automatic airtight feeding device, dust arrester and powder-scraper and turntable, the flying upward property of powder when overcoming direct powder compression and leak the powder phenomenon.
The prior art of valsartan amlodipine sheet is mainly the dry granulation technology of imported product, the technology of new development mainly concentrates on technique of direct powder compression research, the preparation research of dispersible tablet, the aspects such as preparation research of capsule preparations, does not see the correlational study that utilizes domestic the most frequently used wet granule compression tablet technology.The valsartan addition is every 80～320mg in the valsartan amlodipine sheet, and the Amlodipine Besylate Tablet addition is every 5～10mg, belongs to mobile poor, poor compressibility, compound preparation that dosage is bigger.The present invention is on the basis of the medicine composition of deeply and carefully analyzing valsartan amlodipine sheet, consumption, character etc., think that valsartan amlodipine sheet adopts wet granule compression tablet technology to be more suitable for the characteristic of medicine itself, have more science, simultaneously, can overcome the above-mentioned deficiency of technique of direct powder compression.The flowability of valsartan and amlodipine raw material and compressibility are all relatively poor, and both summations proportion in prescription is not suitable for adopting technique of direct powder compression above 51%.
Yet, because factors such as the characteristic of valsartan and amlodipine besylate compound preparation medicine, consumption, adopt the also non-plain sailing of wet granule compression tablet technology, no matter be the kind of disintegrating agent, diluent, lubricant, fluidizer, binding agent etc. and the selection of dosage, still the interpolation order of various adjuvants, addition manner, preparation process etc. have all been carried out great deal of experimental.
Among the present invention, the disintegrate and the stripping of disintegrating agent and valsartan amlodipine medicament composition are closely related.Find that in research process the kind of disintegrating agent is very big to the disintegrate and the stripping influence of valsartan amlodipine medicament composition.Tested multiple disintegrating agents such as cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, the addition trial stretch is 0～50 weight portion.In the technology of wet granulation, adding mode unanimity (in add 50%, add 50%), addition identical (4～15 weight portion), other adjuvant are identical, slice, thin piece hardness is under 5～8kg situation, can obtain ideal disintegrate and result of extraction.Test method and result of the test see Table 1, and the result shows that outward appearance is all good, disintegration respectively less than 1min, greater than 30min with greater than 30min.Therefore, preferred disintegrating agent is a cross-linking sodium carboxymethyl cellulose, and the addition in prescription is 4～15 weight portions.
Among the present invention, the adding mode of disintegrating agent and the disintegrate and the stripping of valsartan amlodipine medicament composition are closely related.In research process, find, with disintegrating agent all join granulate before or all join granulation after all can not obtain ideal disintegrate and stripping.Add 0: 100～100: 0 research of weight ratio by disintegrating agent before and after granulating, before obtaining to granulate (in add) and granulate after (adding) respectively add 50% disintegrate and the optimal conclusion of stripping.
Different disintegrating agents of table 1 and addition are to the influence of disintegrate and stripping
Among the present invention, the disintegrate and the stripping of diluent and valsartan amlodipine medicament composition are closely related.Find that in research process the kind of diluent is very big to the disintegrate and the stripping influence of valsartan amlodipine medicament composition.Plurality of diluent and combinations thereof such as microcrystalline Cellulose, microcrystalline Cellulose+pregelatinized Starch, microcrystalline Cellulose+lactose have been tested, in the technology of wet granulation, adding mode unanimity, addition identical (50～75 weight portion), other adjuvant are identical, slice, thin piece hardness is under 5～8kg situation, test method and result of the test see Table 2, the result shows, outward appearance is all good, is respectively disintegration less than 1min, 3～5min and 11～15min.Therefore, preferred diluent microcrystalline Cellulose, the addition in prescription are 50～75 weight portions.
Different diluent of table 2 and addition thereof are to the influence of disintegrate and stripping
Among the present invention, the disintegrate and the stripping of slice, thin piece hardness and valsartan amlodipine medicament composition are closely related.Find that in research process slice, thin piece hardness is very big to the disintegrate and the stripping influence of valsartan amlodipine medicament composition.5～8kg and 9～12kg have been tested, in the technology of wet granulation, under adding mode unanimity, supplementary product kind and the addition same case, test method and result of the test see Table 3, the result shows that outward appearance is all good, is respectively disintegration less than 1min and 10～24min.Therefore, preferred slice, thin piece hardness 5～8kg.
Table 3 slice, thin piece hardness is to the influence of disintegrate and stripping
Among the present invention, the disintegrate and the stripping of binding agent and valsartan amlodipine medicament composition are closely related.Find that in research process binding agent is remarkable to the disintegrate and the stripping influence of valsartan amlodipine medicament composition.Copolyvidone, carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose 15CP, hydroxypropyl emthylcellulose E15 and hydroxypropyl cellulose L have been tested, in the technology of wet granulation, adding mode unanimity, other supplementary product kind are identical with addition, under slice, thin piece hardness 5～8kg situation, result of the test shows copolyvidone, carboxymethyl cellulose and methylcellulose as binding agent, and disintegrate and result of extraction are all bad; And as table 4 result, hydroxypropyl emthylcellulose 15CP, hydroxypropyl emthylcellulose E15 and hydroxypropyl cellulose L make binding agent, and disintegrate and result of extraction are all more satisfactory, and the outward appearance of sample is all good, are respectively disintegration less than 1min and 10～24min.Wherein, hydroxypropyl emthylcellulose 15CP or hydroxypropyl emthylcellulose E15 are as the binding agent optimum.
Table 4 binding agent kind and consumption are to the influence of disintegrate and stripping
Specific embodiments
Below by concrete preferred implementation the present invention is further described, but does not therefore limit the present invention among the described scope of embodiments.
The present invention finally need be prepared into valsartan amlodipine sheet and use, and enumerates embodiment according to per 1000 tablets of medicines calculating below prescription and production technology are further specified.
Embodiment 1:
1, valsartan amlodipine sheet is 1000, and specification is every valsartan 80mg and Amlodipine Besylate Tablet 5mg, and it is composed as follows to fill a prescription:
Valsartan 80g,
Amlodipine Besylate Tablet (in amlodipine) 5g,
Microcrystalline Cellulose 50g,
Cross-linking sodium carboxymethyl cellulose 4g,
Hydroxypropyl emthylcellulose E15 1.5g,
Magnesium stearate 0.5g,
Silica 1 g.
2, adopt following method to prepare valsartan amlodipine Film coated tablets:
1) valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose are crossed 80 mesh sieves respectively, standby;
2) hydroxypropyl emthylcellulose is mixed with 2% solution with purified water, standby;
3) take by weighing above-mentioned standby valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose and 1/2 cross-linking sodium carboxymethyl cellulose according to recipe quantity, adopt the equivalent method of progressively increasing to mix evenly, add standby Gonak then, mix, until forming single-size, obtain wet granular;
4) with dry 4 hours dryings under 50～60 ℃ of conditions of wet granular, obtain dried granule, moisture is lower than 3%; Dried granule is crossed 20 mesh sieves;
5) magnesium stearate, silicon dioxide and residue 1/2 cross-linking sodium carboxymethyl cellulose and dried granule are adopted the equivalent method mix homogeneously that progressively increases, obtain pharmaceutical composition;
6) resulting pharmaceutical composition is carried out direct pressed powder (5kg), usefulness employing Opadry 03B68903 coating, obtain described Film coated tablets.
3, testing result: outward appearance is good, uniformity of dosage units is 15 for the 5.9(limit), single assorted content is 0.5% for the 0.03%(limit), total assorted for the 0.07%(limit be 2.0%), the dissolution of amlodipine is that 98%～104%(limit is greater than 75%), the dissolution of valsartan is that 97%～99%(limit is greater than 75%), amlodipine content is greater than 95%～105% for the 100.6%(limit), valsartan content is greater than 95%～105% for the 101.5%(limit), other index is all up to specification.
Embodiment 2:
1, valsartan amlodipine sheet is 1000, and specification is every valsartan 80mg and Amlodipine Besylate Tablet 5mg, and it is composed as follows to fill a prescription:
Valsartan 80g,
Amlodipine Besylate Tablet (in amlodipine) 5g,
Microcrystalline Cellulose 75g,
Cross-linking sodium carboxymethyl cellulose 15g,
Hydroxypropyl emthylcellulose E15 3g,
Magnesium stearate 1.5g,
Silicon dioxide 2g.
2, adopt following method to prepare valsartan amlodipine Film coated tablets:
1) valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose are crossed 100 mesh sieves respectively, standby;
2) hydroxypropyl emthylcellulose is mixed with 5% solution with purified water, standby;
3) take by weighing above-mentioned standby valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose and 1/2 cross-linking sodium carboxymethyl cellulose according to recipe quantity, adopt the equivalent method of progressively increasing to mix evenly, add standby Gonak then, mix, until forming single-size, obtain wet granular;
4) with dry 1 hour drying under 60～80 ℃ of conditions of wet granular, obtain dried granule, moisture is lower than 3%; Dried granule is crossed 30 mesh sieves;
5) magnesium stearate, silicon dioxide and residue 1/2 cross-linking sodium carboxymethyl cellulose and dried granule are adopted the equivalent method mix homogeneously that progressively increases, obtain pharmaceutical composition;
6) resulting pharmaceutical composition is carried out direct pressed powder (8kg), usefulness employing Opadry 03B68903 coating, obtain described Film coated tablets.
3, testing result: outward appearance is good, uniformity of dosage units is 15 for the 8.6(limit), single assorted content is 0.5% for the 0.03%(limit), total assorted for the 0.06%(limit be 2.0%), the dissolution of amlodipine is that 96%～103%(limit is greater than 75%), the dissolution of valsartan is that 95%～100%(limit is greater than 75%), amlodipine content is greater than 95%～105% for the 100.7%(limit), valsartan content is greater than 95%～105% for the 101.8%(limit), other index is all up to specification.
Embodiment 3:
1, valsartan amlodipine sheet is 1000, and specification is every valsartan 80mg and Amlodipine Besylate Tablet 5mg, and it is composed as follows to fill a prescription:
Valsartan 80g,
Amlodipine Besylate Tablet (in amlodipine) 5g,
Microcrystalline Cellulose 65g,
Cross-linking sodium carboxymethyl cellulose 13.6g,
Hydroxypropyl emthylcellulose 15CP 2.3g,
Magnesium stearate 0.8g,
Silica 1 .5g.
2, adopt following method to prepare valsartan amlodipine Film coated tablets:
1) valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose are crossed 90 mesh sieves respectively, standby;
2) hydroxypropyl emthylcellulose is mixed with 5% solution with purified water, standby;
3) take by weighing above-mentioned standby valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose and 1/2 cross-linking sodium carboxymethyl cellulose according to recipe quantity, adopt the equivalent method of progressively increasing to mix evenly, add standby Gonak then, mix, until forming single-size, obtain wet granular;
4) with dry 2 hours dryings under 60～70 ℃ of conditions of wet granular, obtain dried granule, moisture is lower than 3%; Dried granule is crossed 40 mesh sieves;
5) magnesium stearate, silicon dioxide and residue 1/2 cross-linking sodium carboxymethyl cellulose and dried granule are adopted the equivalent method mix homogeneously that progressively increases, obtain pharmaceutical composition;
6) resulting pharmaceutical composition is carried out direct pressed powder (7kg), usefulness employing Opadry 03B68903 coating, obtain described Film coated tablets.
3, testing result: outward appearance is good, uniformity of dosage units is 15 for the 5.6(limit), single assorted content is 0.5% for the 0.03%(limit), total assorted for the 0.06%(limit be 2.0%), the dissolution of amlodipine is that 96%～105%(limit is greater than 75%), the dissolution of valsartan is that 96%～99%(limit is greater than 75%), amlodipine content is greater than 95%～105% for the 100.2%(limit), valsartan content is greater than 95%～105% for the 101.3%(limit), other index is all up to specification.
Embodiment 4:
1, valsartan amlodipine sheet is 1000, and specification is every valsartan 80mg and Amlodipine Besylate Tablet 5mg, and it is composed as follows to fill a prescription:
Valsartan 80g
Amlodipine Besylate Tablet (in amlodipine) 5g
Microcrystalline Cellulose 70g
Cross-linking sodium carboxymethyl cellulose 5g
Hydroxypropyl emthylcellulose E15 2g
Magnesium stearate 0.8g
Silica 1 .5g
2, adopt following method to prepare valsartan amlodipine Film coated tablets:
1) valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose are crossed 80 mesh sieves respectively, standby;
2) hydroxypropyl emthylcellulose is mixed with 3% solution with purified water, standby;
3) take by weighing above-mentioned standby valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose and 1/2 cross-linking sodium carboxymethyl cellulose according to recipe quantity, adopt the equivalent method of progressively increasing to mix evenly, add standby Gonak then, mix, until forming single-size, obtain wet granular;
4) with dry 3 hours dryings under 50～60 ℃ of conditions of wet granular, obtain dried granule, moisture is lower than 3%; Dried granule is crossed 20 mesh sieves;
5) magnesium stearate, silicon dioxide and residue 1/2 cross-linking sodium carboxymethyl cellulose and dried granule are adopted the equivalent method mix homogeneously that progressively increases, obtain pharmaceutical composition;
6) resulting pharmaceutical composition is carried out direct pressed powder (6kg), usefulness employing Opadry 03B68903 coating, obtain described Film coated tablets.
3, testing result: outward appearance is good, uniformity of dosage units is 15 for the 5.8(limit), single assorted content is 0.5% for the 0.03%(limit), total assorted for the 0.07%(limit be 2.0%), the dissolution of amlodipine is that 97%～104%(limit is greater than 75%), the dissolution of valsartan is that 96%～101%(limit is greater than 75%), amlodipine content is greater than 95%～105% for the 100.5%(limit), valsartan content is greater than 95%～105% for the 101.6%(limit), other index is all up to specification.
Embodiment 5:
1, valsartan amlodipine sheet is 1000, and specification is every valsartan 160mg and Amlodipine Besylate Tablet 5mg, and it is composed as follows to fill a prescription:
Valsartan 160g
Amlodipine Besylate Tablet (in amlodipine) 5g
Microcrystalline Cellulose 140g
Cross-linking sodium carboxymethyl cellulose 10g
Hydroxypropyl emthylcellulose E15 4g
Magnesium stearate 1.6g
Silicon dioxide 3g
2, adopt following method to prepare valsartan amlodipine Film coated tablets:
1) valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose are crossed 80 mesh sieves respectively, standby;
2) hydroxypropyl emthylcellulose is mixed with 3% solution with purified water, standby;
3) take by weighing above-mentioned standby valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose and 1/2 cross-linking sodium carboxymethyl cellulose according to recipe quantity, adopt the equivalent method of progressively increasing to mix evenly, add standby Gonak then, mix, until forming single-size, obtain wet granular;
4) with dry 3 hours dryings under 50～60 ℃ of conditions of wet granular, obtain dried granule, moisture is lower than 3%; Dried granule is crossed 30 mesh sieves;
5) magnesium stearate, silicon dioxide and residue 1/2 cross-linking sodium carboxymethyl cellulose and dried granule are adopted the equivalent method mix homogeneously that progressively increases, obtain pharmaceutical composition;
6) resulting pharmaceutical composition is carried out direct pressed powder (8kg), usefulness employing Opadry 03B68903 coating, obtain described Film coated tablets.
3, testing result: outward appearance is good, uniformity of dosage units is 15 for the 6.8(limit), single assorted content is 0.5% for the 0.03%(limit), total assorted for the 0.08%(limit be 2.0%), the dissolution of amlodipine is that 96%～103%(limit is greater than 75%), the dissolution of valsartan is that 97%～100%(limit is greater than 75%), amlodipine content is greater than 95%～105% for the 101.5%(limit), valsartan content is greater than 95%～105% for the 101.1%(limit), other index is all up to specification.
Embodiment 6:
1, valsartan amlodipine sheet is 1000, and specification is every valsartan 160mg and Amlodipine Besylate Tablet 10mg, and it is composed as follows to fill a prescription:
Valsartan 160g
Amlodipine Besylate Tablet (in amlodipine) 10g
Microcrystalline Cellulose 140g
Cross-linking sodium carboxymethyl cellulose 10g
Hydroxypropyl emthylcellulose 15CP 4g
Magnesium stearate 1.6g
Silicon dioxide 3g
2, adopt following method to prepare valsartan amlodipine Film coated tablets:
1) valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose are crossed 80 mesh sieves respectively, standby;
2) hydroxypropyl emthylcellulose is mixed with 3% solution with purified water, standby;
3) take by weighing above-mentioned standby valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose and 1/2 cross-linking sodium carboxymethyl cellulose according to recipe quantity, adopt the equivalent method of progressively increasing to mix evenly, add standby Gonak then, mix, until forming single-size, obtain wet granular;
4) with dry 3 hours dryings under 50～60 ℃ of conditions of wet granular, obtain dried granule, moisture is lower than 3%; Dried granule is crossed 40 mesh sieves;
5) magnesium stearate, silicon dioxide and residue 1/2 cross-linking sodium carboxymethyl cellulose and dried granule are adopted the equivalent method mix homogeneously that progressively increases, obtain pharmaceutical composition;
6) resulting pharmaceutical composition is carried out direct pressed powder (8kg), usefulness employing Opadry 03B68903 coating, obtain described Film coated tablets.
3, testing result: outward appearance is good, uniformity of dosage units is 15 for the 7.2(limit), single assorted content is 0.5% for the 0.03%(limit), total assorted for the 0.07%(limit be 2.0%), the dissolution of amlodipine is that 97%～104%(limit is greater than 75%), the dissolution of valsartan is that 96%～100%(limit is greater than 75%), amlodipine content is greater than 95%～105% for the 101.1%(limit), valsartan content is greater than 95%～105% for the 100.1%(limit), other index is all up to specification.
Embodiment 7:
1, valsartan amlodipine sheet is 1000, and specification is every valsartan 320mg and Amlodipine Besylate Tablet 10mg, and it is composed as follows to fill a prescription:
Valsartan 320g
Amlodipine Besylate Tablet (in amlodipine) 10g
Microcrystalline Cellulose 280g
Cross-linking sodium carboxymethyl cellulose 20g
Hydroxypropyl emthylcellulose E15 8g
Magnesium stearate 3.2g
Silicon dioxide 6g
2, adopt following method to prepare valsartan amlodipine Film coated tablets:
1) valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose are crossed 100 mesh sieves respectively, standby;
2) hydroxypropyl emthylcellulose is mixed with 5% solution with purified water, standby;
3) take by weighing above-mentioned standby valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose and 1/2 cross-linking sodium carboxymethyl cellulose according to recipe quantity, adopt the equivalent method of progressively increasing to mix evenly, add standby Gonak then, mix, until forming single-size, obtain wet granular;
4) with dry 2 hours dryings under 60～70 ℃ of conditions of wet granular, obtain dried granule, moisture is lower than 3%; Dried granule is crossed 20 mesh sieves;
5) magnesium stearate, silicon dioxide and residue 1/2 cross-linking sodium carboxymethyl cellulose and dried granule are adopted the equivalent method mix homogeneously that progressively increases, obtain pharmaceutical composition;
6) resulting pharmaceutical composition is carried out direct pressed powder (8kg), usefulness employing Opadry 03B68903 coating, obtain described Film coated tablets.
3, testing result: outward appearance is good, uniformity of dosage units is 15 for the 7.5(limit), single assorted content is 0.5% for the 0.03%(limit), total assorted for the 0.09%(limit be 2.0%), the dissolution of amlodipine is that 95%～102%(limit is greater than 75%), the dissolution of valsartan is that 97%～101%(limit is greater than 75%), amlodipine content is greater than 95%～105% for the 101.8%(limit), valsartan content is greater than 95%～105% for the 101.5%(limit), other index is all up to specification.
Embodiment 8:
1, valsartan amlodipine sheet is 1000, and specification is every valsartan 320mg and Amlodipine Besylate Tablet 5mg, and it is composed as follows to fill a prescription:
Valsartan 320g
Amlodipine Besylate Tablet (in amlodipine) 5g
Microcrystalline Cellulose 280g
Cross-linking sodium carboxymethyl cellulose 20g
Hydroxypropyl emthylcellulose E15 8g
Magnesium stearate 3.2g
Silicon dioxide 6g
2, adopt following method to prepare valsartan amlodipine Film coated tablets:
1) valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose are crossed 100 mesh sieves respectively, standby;
2) hydroxypropyl emthylcellulose is mixed with 5% solution with purified water, standby;
3) take by weighing above-mentioned standby valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose and 1/2 cross-linking sodium carboxymethyl cellulose according to recipe quantity, adopt the equivalent method of progressively increasing to mix evenly, add standby Gonak then, mix, until forming single-size, obtain wet granular;
4) with dry 2 hours dryings under 60～70 ℃ of conditions of wet granular, obtain dried granule, moisture is lower than 3%; Dried granule is crossed 20 mesh sieves;
5) magnesium stearate, silicon dioxide and residue 1/2 cross-linking sodium carboxymethyl cellulose and dried granule are adopted the equivalent method mix homogeneously that progressively increases, obtain pharmaceutical composition;
6) resulting pharmaceutical composition is carried out direct pressed powder (8kg), usefulness employing Opadry 03B68903 coating, obtain described Film coated tablets.
3, testing result: outward appearance is good, uniformity of dosage units is 15 for the 6.5(limit), single assorted content is 0.5% for the 0.03%(limit), total assorted for the 0.07%(limit be 2.0%), the dissolution of amlodipine is that 97%～103%(limit is greater than 75%), the dissolution of valsartan is that 96%～100%(limit is greater than 75%), amlodipine content is greater than 95%～105% for the 100.8%(limit), valsartan content is greater than 95%～105% for the 100.5%(limit), other index is all up to specification.
Embodiment 9:Stability test research
Utilize the sample of the invention described above the foregoing description 1～embodiment 8 to carry out stability test.
Experimental condition and time: lucifuge, 40 ℃, 6 months.
Detect index: outward appearance, single assorted content, always assorted content, dissolution, drug content etc.
Result of the test: in 6 months, the outward appearance of embodiment 1～embodiment 8 samples, single assorted content, always assorted content, dissolution, drug content all do not have significant change, and the conformance with standard regulation all embodies good stable.Each sample dissolution of 15 minutes in pH6.8 phosphate buffer+0.1% Tween 80, water, pH6.8 phosphate buffer, 0.1M hydrochloric acid and pH4.5 phosphate buffer embodies good disintegrate and dissolution characteristic all greater than 95%.
Embodiment 10:The bioequivalence experimental study
Utilize the sample of the invention described above the foregoing description 1～embodiment 8 to carry out stability test.
Test(ing) medium: A, pH6.8 phosphate buffer+0.1% Tween 80; B, water; C, pH6.8 phosphate buffer; D, 0.1M hydrochloric acid; E, pH4.5 phosphate buffer.
Detect index: dissolution.
Result of the test: in oral administration solid medicine bioavailability in 1999 and bioequivalence Journal of Sex Research guide, recommend to use the similar factors method to estimate the dissolution of embodiment 1～embodiment 8 samples according to FDA, the similar factors f2 of the dissolution of embodiment 1～embodiment 8 samples in above-mentioned A, B, C, D and E medium and listing product dissolution is all greater than 50, therefore, embodiment 1～embodiment 8 samples have bioequivalence with the listing product among the present invention.
Claims (9)
1. a valsartan amlodipine medicament composition is characterized in that, described pharmaceutical composition is made up of the composition of raw materials of following weight portion:
Valsartan 80,
Amlodipine Besylate Tablet (in amlodipine) 5,
Microcrystalline Cellulose 50～75,
Cross-linking sodium carboxymethyl cellulose 4～15,
Hydroxypropyl emthylcellulose 1.5～3,
Magnesium stearate 0.5～1.5,
Silica 1～2.
2. valsartan amlodipine medicament composition according to claim 1 is characterized in that, described pharmaceutical composition is made up of the prescription of following weight portion:
Valsartan 80,
Amlodipine Besylate Tablet (in amlodipine) 5,
Microcrystalline Cellulose 65,
Cross-linking sodium carboxymethyl cellulose 13.6,
Hydroxypropyl emthylcellulose 2.3,
Magnesium stearate 0.8,
Silica 1 .5.
3. valsartan amlodipine medicament composition according to claim 1 is characterized in that, described pharmaceutical composition is made up of the prescription of following weight portion:
Valsartan 80,
Amlodipine Besylate Tablet (in amlodipine) 5,
Microcrystalline Cellulose 70,
Cross-linking sodium carboxymethyl cellulose 5,
Hydroxypropyl emthylcellulose 2,
Magnesium stearate 0.8,
Silica 1 .5.
4. according to claim 1 or 2 or 3 described valsartan amlodipine medicament compositions, it is characterized in that described hydroxypropyl emthylcellulose is preferably a kind of of hydroxypropyl emthylcellulose E15 and hydroxypropyl emthylcellulose 15CP.
5. the preparation method of valsartan amlodipine medicament composition is characterized in that, according to the prescription of the arbitrary weight portion of claim 1～4, concrete steps comprise:
1) valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose are sieved respectively, standby;
2) with purified water hydroxypropyl emthylcellulose is mixed with solution, standby;
3) take by weighing above-mentioned standby valsartan, Amlodipine Besylate Tablet, microcrystalline Cellulose and partial cross-linked sodium carboxymethyl cellulose according to recipe quantity, mix homogeneously adds standby Gonak then, mixes, until forming single-size, obtain wet granular;
4) with wet grain drying, obtain dried granule, dried granule granulate, standby;
5) with magnesium stearate, silicon dioxide and residue cross-linking sodium carboxymethyl cellulose and dried granule mix homogeneously, obtain pharmaceutical composition;
6) resulting pharmaceutical composition is carried out direct pressed powder, coating, obtain described Film coated tablets.
6. preparation method according to claim 5 is characterized in that, sieving to crossing 80～100 mesh sieves described in the step 1); Step 2) Gonak described in is 2～5% hypromellose aqueous solution; The amount of the partial cross-linked sodium carboxymethyl cellulose described in the step 3) is 1/2nd of a recipe quantity.
7. preparation method according to claim 5 is characterized in that, the drying described in the step 4) is under 50～80 ℃ of conditions dry 1～4 hour; Described dried particulate moisture is below 3%; Described granulate was meant 20～40 mesh sieves.
8. preparation method according to claim 5 is characterized in that, step 3) and 5) described in mix homogeneously adopt the equivalent method of progressively increasing to carry out.
9. preparation method according to claim 5 is characterized in that, the tabletting described in the step 6) is at 5～8kg with the slice, thin piece Hardness Control; Described coating is that the coating solution that adopts Opadry 03B68903 and purified water to form carries out coating.
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| CN105213388A (en) * | 2015-11-19 | 2016-01-06 | 哈尔滨圣吉药业股份有限公司 | A kind of valsartan/azelnidipine oral formulations and preparation method thereof |
| CN105232551A (en) * | 2015-11-19 | 2016-01-13 | 哈尔滨圣吉药业股份有限公司 | Valsartan and levamlodpine besylate compound preparation and preparation method thereof |
| CN108721241A (en) * | 2017-04-18 | 2018-11-02 | 江苏恒瑞医药股份有限公司 | A kind of solid composite and preparation method thereof including Valsartan and Amlodipine |
| CN108785267A (en) * | 2018-08-14 | 2018-11-13 | 北京百奥药业有限责任公司 | A kind of valsartan amlodipine piece and preparation method thereof |
| CN114917225A (en) * | 2022-03-16 | 2022-08-19 | 黄山中皇制药有限公司 | Preparation method and preparation device of valsartan levamlodipine composition |
| CN114917226A (en) * | 2022-03-16 | 2022-08-19 | 黄山中皇制药有限公司 | Valsartan levamlodipine composition |
| CN114917224A (en) * | 2022-03-16 | 2022-08-19 | 黄山中皇制药有限公司 | Production and batching process and batching equipment for valsartan levamlodipine composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105213388A (en) * | 2015-11-19 | 2016-01-06 | 哈尔滨圣吉药业股份有限公司 | A kind of valsartan/azelnidipine oral formulations and preparation method thereof |
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| CN108721241A (en) * | 2017-04-18 | 2018-11-02 | 江苏恒瑞医药股份有限公司 | A kind of solid composite and preparation method thereof including Valsartan and Amlodipine |
| CN108785267A (en) * | 2018-08-14 | 2018-11-13 | 北京百奥药业有限责任公司 | A kind of valsartan amlodipine piece and preparation method thereof |
| CN108785267B (en) * | 2018-08-14 | 2020-05-19 | 北京百奥药业有限责任公司 | Valsartan amlodipine tablet and preparation method thereof |
| CN114917225A (en) * | 2022-03-16 | 2022-08-19 | 黄山中皇制药有限公司 | Preparation method and preparation device of valsartan levamlodipine composition |
| CN114917226A (en) * | 2022-03-16 | 2022-08-19 | 黄山中皇制药有限公司 | Valsartan levamlodipine composition |
| CN114917224A (en) * | 2022-03-16 | 2022-08-19 | 黄山中皇制药有限公司 | Production and batching process and batching equipment for valsartan levamlodipine composition |
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