CN102138920A - Medicinal composition containing candesartan cilexetil and hydrochlorothiazide and preparation method thereof - Google Patents
Medicinal composition containing candesartan cilexetil and hydrochlorothiazide and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a medicinal composition containing candesartan cilexetil and hydrochlorothiazide and a preparation method thereof. The medicinal composition comprises the following components in parts by weight: 4 or 8 parts of candesartan cilexetil, 6.25 parts of hydrochlorothiazide, 60 to 100 parts of lactose monohydrate, 15 to 40 parts of microcrystalline cellulose, 2.6 parts of croscarmellose sodium, 2.6 parts of polyglycol 6000, and 1.3 parts of magnesium stearate. After the medicinal composition is uniformly mixed, an 8 percent high-substitution hydroxypropyl cellulose aqueous solution is used as a binder to granulate by a wet method and to tablet. In the method, by adopting a certain amount of the polyglycol 6000 as a stabilizer, the preparation stability is remarkably improved; and over 90 percent of dissolution rate can be achieved in 45 minutes by adopting less disintegrant and binder; the preparation method has a simple production process without adding extra equipment; the tablets produced according to the method has good stability and high disintegration speed, so that the dissolution of the medicament is remarkably improved, and measurement proves that: the dissolution of the tablets prepared by adopting the method reaches over 90 percent in 45 minutes.
Description
Technical field
The invention belongs to technical field of medicine, relate to a kind of pharmaceutical composition that contains candesartan Cilexetil and hydrochlorothiazide and preparation method thereof.
Background technology
Hypertension is modal cardiovascular disease, is the great public health difficult problem in the worldwide.Treating hypertensive main purpose is to reduce cardiovascular morbidity and mortality rate risk to greatest extent.At present, whole world hypertension prevalence is 31.3%, dies from hypertension relevant disease person every year and accounts for 6% of the dead population in the world.Hypertension is one of most important independent hazard factor of cardiovascular disease, normal and dyslipidemia, insulin resistant, diabetes or obesity etc. are also deposited, cause important target organ damages such as the heart, brain, kidney, and closely related with cardiovascular events such as apoplexy, coronary heart disease, nephropathy.
Controlling of blood pressure is up to standard to be the core of blood pressure lowering therapeutic strategy.In order at utmost to reach the hypertensive effect of treatment, many clinically single antihypertensive drugs often follow untoward reaction to occur or increase after increasing dosage, make the patient be difficult to tolerance, and often can not make blood pressure reduce to ideal level, best therapeutic scheme is exactly a drug combination.Randomized clinical trial proves that most of hyperpietics must use two or more depressor for controlling blood pressure, and share medicine has its necessary and value.Situation about not increasing every kind of pharmaceutical quantities when share medicine, the therapeutical effect of two or more depressor have the effect of collaborative or addition, and its untoward reaction can be cancelled out each other or not overlapping at least or addition, helps increasing patient tolerability and improves compliance.
One of the principal agent of this pharmaceutical composition candesartan Cilexetil (candesartan cilexetil) is Angiotensin II inhibitor (ARB), and 1999 in Japan listing, becomes the first ARB that can be used for chronic heart failure of Japan in 2005.Candesartan Cilexetil is incorporated into vasoconstriction and the aldosterone secretory action that the AT1 receptor suppresses Angiotensin II by the Angiotensin II that selectivity blocks in many tissues (as vascular smooth muscle and adrenal gland etc.).The hydrochlorothiazide of the principal agent of this pharmaceutical composition (hydrochlorothiazide) is a thiazide diuretic, urinates by increase and reduces the extracellular fluid volume and bring high blood pressure down.
Have now and studies show that ARB and thiazide diuretic hydrochlorothiazide share obviously synergism, disclose a kind of losartan potassium hydrochlorothiazide composition and preparation method thereof as patent documentation CN 101632678; Patent of invention CN 101766600A discloses a kind of compound candesartan cilexetil preparation and preparation method thereof, and its formulation characteristics is that unit formulation is by candesartan Cilexetil 32mg/ hydrochlorothiazide 12.5mg; Candesartan Cilexetil 16mg/ hydrochlorothiazide 12.5mg and adjuvant are formed, and specification is bigger, is not suitable for Chinese population; Its adjuvant does not add the stabilizing agent polyethylene glycol 6000 by starch, microcrystalline Cellulose, lactose and carboxymethyl starch sodium, carboxy-propyl cellulose, hydroxypropyl emthylcellulose, crospolyvinylpyrrolidone and cross-linking sodium carboxymethyl cellulose in addition.
The Chinese granted patent CN 1047518C (expire in November, 2011) of Japan Takede Chemical Industries Ltd relates to the preparation method of combination of oral medication, points out that candesartan Cilexetil mixes back mold pressing gained preparation and will get well with respect to the preparation stability that does not add the low melting point oiliness compound with the low melting point oiliness compound.The preferred in an embodiment polyethylene glycol 6000 of this patent is as the low melting point oiliness compound, but consumption is 6.0 weight portions, and numerical value is bigger, and the preparation dissolution is not good enough.
Shortcoming at foregoing invention, the inventor has carried out optimizing and revising of prescription and technology to the tablet that contains candesartan Cilexetil and hydrochlorothiazide, adopt more a spot of polyethylene glycol 6000 used as stabilizers, simultaneously preferred cross-linking sodium carboxymethyl cellulose is as best disintegrating agent, the tablet stability of preparing is good, disintegrate and stripping are rapid, after measured, adopt the tablet 45min stripping of method preparation of the present invention to reach more than 90%.
Summary of the invention
First purpose of the present invention is to provide a kind of pharmaceutical composition that contains candesartan Cilexetil and hydrochlorothiazide, the preferred amount of the poly-ethanol 6000 of stabilizing agent, Chinese granted patent CN 1047518C with respect to Japanese Takede Chemical Industries Ltd, reduced its consumption over half, greatly reduce production cost, when guaranteeing stability, more help the disintegrate and the stripping of tablet.
Second purpose of the present invention has been to provide a kind of preparation of drug combination method that contains candesartan Cilexetil and hydrochlorothiazide, and the pharmaceutical composition of using the preparation of this method has and has good stability, and disintegrate is faster, and helps to improve the advantage of the stripping of medicine.
For realizing first purpose of the present invention, the present invention adopts following technical scheme:
The pharmaceutical composition of a kind of candesartan Cilexetil and hydrochlorothiazide, wherein, described pharmaceutical composition is made up of following prescription:
| Candesartan Cilexetil | 4 or 8 weight portions |
| Hydrochlorothiazide | 6.25 weight portion |
| Lactose monohydrate | 60～100 weight portions |
| Microcrystalline Cellulose | 15～40 weight portions |
| Cross-linking sodium carboxymethyl cellulose | 2.6 weight portion |
| Polyethylene glycol 6000 | 2.6～5.2 weight portions |
| Magnesium stearate | 1.3 weight portion |
| 8% Hydroxypropylcelliloxe aqueous solution | In right amount |
Preferably, described pharmaceutical composition is made up of following prescription:
| Candesartan Cilexetil | 4 or 8 weight portions |
| Hydrochlorothiazide | 6.25 weight portion |
| Lactose monohydrate | 80 weight portions |
| Microcrystalline Cellulose | 30 weight portions |
| Cross-linking sodium carboxymethyl cellulose | 2.6 weight portion |
| Polyethylene glycol 6000 | 2.6 weight portion |
| Magnesium stearate | 1.3 weight portion |
| 8% Hydroxypropylcelliloxe aqueous solution | In right amount |
According to aforesaid pharmaceutical composition, wherein, described pharmaceutical composition is a tablet.
According to aforesaid pharmaceutical composition, wherein, described tablet is to adopt following method preparation:
1) candesartan Cilexetil, hydrochlorothiazide are sieved respectively, standby;
2) lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, magnesium stearate, Hydroxypropylcelliloxe are sieved respectively, standby;
3) take by weighing the prescription inventory candesartan Cilexetil, hydrochlorothiazide, lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and polyethylene glycol 6000, mix homogeneously obtains the hybrid medicine powder;
4) get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, the granulation of sieving, after the wet granular oven dry, granulate sieves;
5) take by weighing the magnesium stearate of prescription inventory, join in the material behind the above-mentioned granulate, carry out always mixing, obtain described pharmaceutical composition;
6) resulting pharmaceutical composition is carried out tabletting.
For realizing second purpose of the present invention, the present invention adopts following technical scheme:
A kind of described preparation of drug combination method, this method comprises:
1) candesartan Cilexetil, hydrochlorothiazide are sieved respectively, standby;
2) lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, magnesium stearate, Hydroxypropylcelliloxe are sieved respectively, standby;
3) take by weighing the prescription inventory candesartan Cilexetil, hydrochlorothiazide, lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and polyethylene glycol 6000, mix homogeneously obtains the hybrid medicine powder;
4) get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, the granulation of sieving, after the wet granular oven dry, granulate sieves;
5) take by weighing the magnesium stearate of prescription inventory, join in the material behind the above-mentioned granulate, carry out always mixing, obtain described pharmaceutical composition.
According to aforesaid preparation method, wherein, described preparation method also further comprises carries out tabletting with resulting pharmaceutical composition.
According to aforesaid preparation method, wherein, step 1) is described sieves to crossing 80～100 mesh sieves.
According to aforesaid preparation method, wherein, step 2) described sieving to crossing 60～80 mesh sieves.
According to aforesaid preparation method, wherein, in the step 3), described mixing carries out mixing for adopting the equivalent method of progressively increasing.
According to aforesaid preparation method, wherein, in the step 3), described drying condition is for to dry by the fire 2～4 hours under 60～80 ℃ of conditions, and the described granulate that sieves is meant 20 eye mesh screen granulate.
According to aforesaid preparation method, wherein said tabletting is at 5～8kg with the slice, thin piece Hardness Control.
Below be detailed description of the present invention:
One aspect of the present invention provides the pharmaceutical composition of a kind of candesartan Cilexetil and hydrochlorothiazide, and this pharmaceutical composition has and has good stability, and disintegrate is faster, thereby helps to improve the advantage of drug dissolution.
Pharmaceutical composition provided by the invention is made up of following prescription:
| Candesartan Cilexetil | 4 or 8 weight portions |
| Hydrochlorothiazide | 6.25 weight portion |
| Lactose monohydrate | 60～100 weight portions |
| Microcrystalline Cellulose | 15～40 weight portions |
| Cross-linking sodium carboxymethyl cellulose | 2.6 weight portion |
| Polyethylene glycol 6000 | 2.6～5.2 weight portions |
| Magnesium stearate | 1.3 weight portion |
| 8% Hydroxypropylcelliloxe aqueous solution | In right amount |
Publication number is that the Chinese patent application of CN 101766600 A discloses a kind of capsule or tablet that contains candesartan Cilexetil and hydrochlorothiazide, and used disintegrating agent is a polyvinylpolypyrrolidone, and content is about 10% of this solid dosage forms.Because polyvinylpolypyrrolidone has and extremely strong draws moistly, candesartan Cilexetil that it is prepared and Aquazide H or capsule stability are relatively poor, and disintegrate and stripping are slower.
The inventor is after having carried out a large amount of prescription screening tests, and carried out after the test of many times to the consumption of supplementary material, find that preferred cross-linking sodium carboxymethyl cellulose is a disintegrating agent, in consumption was 2～6% scopes of recipe quantity, the stripping of the slice, thin piece that makes can reach more than 90% at 45min; And the dissolution of tablet increases with the increase of cross-linking sodium carboxymethyl cellulose consumption.When its consumption is higher than 6%, continue to increase consumption, dissolution increases not obvious.Gu determine preferred prescription be:
| Candesartan Cilexetil | 4 or 8 weight portions |
| Hydrochlorothiazide | 6.25 weight portion |
| Lactose monohydrate | 80 weight portions |
| Microcrystalline Cellulose | 30 weight portions |
| Cross-linking sodium carboxymethyl cellulose | 2.6 weight portion |
| Polyethylene glycol 6000 | 2.6～5.2 weight portions |
| Magnesium stearate | 1.3 weight portion |
| 8% Hydroxypropylcelliloxe aqueous solution | In right amount |
In addition, the present invention the is preferred consumption of stabilizing agent polyethylene glycol 6000, Chinese granted patent CN 1047518C with respect to Japanese Takede Chemical Industries Ltd, reduced its consumption over half, greatly reduce production cost, when guaranteeing stability, more help the disintegrate and the stripping of tablet.
Another aspect of the present invention provides a kind of wet granule compression tablet method that contains the pharmaceutical composition of candesartan Cilexetil and hydrochlorothiazide of the present invention.The wet granule compression tablet method that we adopt is simple, need not add extras, and can effectively guarantee the uniformity of dosage units of principal agent.
Compared with prior art, the present invention has following advantage:
(1) pharmaceutical composition provided by the present invention has and has good stability, and disintegrate is faster, thereby helps to improve the advantage of medicine stripping;
(2) candesartan Cilexetil is an insoluble drug, and the present invention is preferred disintegrating agent selects for use more a spot of cross-linking sodium carboxymethyl cellulose as disintegrating agent, can guarantee that disintegrate faster can take into account the stripping that medicine is provided again;
(3) the present invention the is preferred consumption of stabilizing agent polyethylene glycol 6000 reduces its consumption over half, and Zhi Bei tablet stability is good after testing, is better than not adding the preparation of stabilizing agent, and is well positioned to meet the production and the storage requirement of preparation.
(4) the present invention adopts tabletting behind the wet granulation, and the method simple possible can effectively guarantee the uniformity of dosage units of principal agent and need not add extras.
The specific embodiment:
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
Embodiment 1
1. write out a prescription
| Candesartan Cilexetil | 8g |
| Hydrochlorothiazide | 6.25g |
| Lactose monohydrate | 80g |
| Microcrystalline Cellulose | 30g |
| Cross-linking sodium carboxymethyl cellulose | 2.6g |
| Polyethylene glycol 6000 | 2.6g |
| Magnesium stearate | 1.3g |
| 8% Hydroxypropylcelliloxe aqueous solution | In right amount |
| Make | 1000 |
2. preparation technology
1) candesartan Cilexetil, hydrochlorothiazide are crossed 80 mesh sieves respectively, standby;
2) lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, magnesium stearate, Hydroxypropylcelliloxe are crossed 60 mesh sieves respectively, standby;
3) take by weighing candesartan Cilexetil, hydrochlorothiazide, lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and the polyethylene glycol 6000 of prescription inventory,, obtain the hybrid medicine powder by the equivalent method mix homogeneously that progressively increases;
4) get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, cross 20 mesh sieves and granulate, wet granular after 2 hours, is crossed 20 mesh sieve granulate in 60 ℃ of oven dry;
5) take by weighing the magnesium stearate of prescription inventory, join in the material behind the above-mentioned granulate, carry out always mixing, obtain described pharmaceutical composition;
6) measure drug content, it is heavy to calculate sheet, carries out tabletting with diameter 8mm punch die, control tablet hardness 6.5kg.
Embodiment 2
1. write out a prescription
| Candesartan Cilexetil | 8g |
| Hydrochlorothiazide | 6.25g |
| Lactose monohydrate | 70g |
| Microcrystalline Cellulose | 40g |
| Cross-linking sodium carboxymethyl cellulose | 2.6g |
| Polyethylene glycol 6000 | 2.6g |
| Magnesium stearate | 1.3g |
| 8% Hydroxypropylcelliloxe aqueous solution | In right amount |
| Make | 1000 |
2. preparation technology
1) candesartan Cilexetil, hydrochlorothiazide are crossed 80 mesh sieves respectively, standby;
2) lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, magnesium stearate, Hydroxypropylcelliloxe are crossed 60 mesh sieves respectively, standby;
3) take by weighing candesartan Cilexetil, hydrochlorothiazide, lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and the polyethylene glycol 6000 of prescription inventory,, obtain the hybrid medicine powder by the equivalent method mix homogeneously that progressively increases;
4) get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, cross 20 mesh sieves and granulate, wet granular after 2 hours, is crossed 20 mesh sieve granulate in 60 ℃ of oven dry;
5) take by weighing the magnesium stearate of prescription inventory, join in the material behind the above-mentioned granulate, carry out always mixing, obtain described pharmaceutical composition;
6) measure drug content, it is heavy to calculate sheet, carries out tabletting with diameter 8mm punch die, control tablet hardness 6.5kg.
Embodiment 3
1. write out a prescription
| Candesartan Cilexetil | 8g |
| Hydrochlorothiazide | 6.25g |
| Lactose monohydrate | 80g |
| Microcrystalline Cellulose | 30g |
| Cross-linking sodium carboxymethyl cellulose | 5.2g |
| Polyethylene glycol 6000 | 2.6g |
| Magnesium stearate | 1.3g |
| 8% Hydroxypropylcelliloxe aqueous solution | In right amount |
| Make | 1000 |
2. preparation technology
1) candesartan Cilexetil, hydrochlorothiazide are crossed 80 mesh sieves respectively, standby;
2) lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, magnesium stearate, Hydroxypropylcelliloxe are crossed 60 mesh sieves respectively, standby;
3) take by weighing candesartan Cilexetil, hydrochlorothiazide, lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and the polyethylene glycol 6000 of prescription inventory,, obtain the hybrid medicine powder by the equivalent method mix homogeneously that progressively increases;
4) get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, cross 20 mesh sieves and granulate, wet granular after 2 hours, is crossed 20 mesh sieve granulate in 60 ℃ of oven dry;
5) take by weighing the magnesium stearate of prescription inventory, join in the material behind the above-mentioned granulate, carry out always mixing, obtain described pharmaceutical composition;
6) measure drug content, it is heavy to calculate sheet, carries out tabletting with diameter 8mm punch die, control tablet hardness 6.5kg.
Embodiment 4
1. write out a prescription
| Candesartan Cilexetil | 4g |
| Hydrochlorothiazide | 6.25g |
| Lactose monohydrate | 80g |
| Microcrystalline Cellulose | 30g |
| Cross-linking sodium carboxymethyl cellulose | 2.6g |
| Polyethylene glycol 6000 | 2.6g |
| Magnesium stearate | 1.3g |
| 8% Hydroxypropylcelliloxe aqueous solution | In right amount |
| Make | 1000 |
2. preparation technology
1) candesartan Cilexetil, hydrochlorothiazide are crossed 80 mesh sieves respectively, standby;
2) lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, magnesium stearate, Hydroxypropylcelliloxe are crossed 60 mesh sieves respectively, standby;
3) take by weighing candesartan Cilexetil, hydrochlorothiazide, lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and the polyethylene glycol 6000 of prescription inventory,, obtain the hybrid medicine powder by the equivalent method mix homogeneously that progressively increases;
4) get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, cross 20 mesh sieves and granulate, wet granular after 2 hours, is crossed 20 mesh sieve granulate in 60 ℃ of oven dry;
5) take by weighing the magnesium stearate of prescription inventory, join in the material behind the above-mentioned granulate, carry out always mixing, obtain described pharmaceutical composition;
6) measure drug content, it is heavy to calculate sheet, carries out tabletting with diameter 8mm punch die, control tablet hardness 8kg.
Embodiment 5
1. write out a prescription
| Candesartan Cilexetil | 8g |
| Hydrochlorothiazide | 6.25g |
| Lactose monohydrate | 80g |
| Microcrystalline Cellulose | 30g |
| Cross-linking sodium carboxymethyl cellulose | 2.6g |
| Polyethylene glycol 6000 | 5.2g |
| Magnesium stearate | 1.3g |
| 8% Hydroxypropylcelliloxe aqueous solution | In right amount |
| Make | 1000 |
2. preparation technology
1) candesartan Cilexetil, hydrochlorothiazide are crossed 80 mesh sieves respectively, standby;
2) lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, magnesium stearate, Hydroxypropylcelliloxe are crossed 60 mesh sieves respectively, standby;
3) take by weighing candesartan Cilexetil, hydrochlorothiazide, lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and the polyethylene glycol 6000 of prescription inventory,, obtain the hybrid medicine powder by the equivalent method mix homogeneously that progressively increases;
4) get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, cross 20 mesh sieves and granulate, wet granular after 2 hours, is crossed 20 mesh sieve granulate in 60 ℃ of oven dry;
5) take by weighing the magnesium stearate of prescription inventory, join in the material behind the above-mentioned granulate, carry out always mixing, obtain described pharmaceutical composition;
6) measure drug content, it is heavy to calculate sheet, carries out tabletting with diameter 8mm punch die, control tablet hardness 6.5kg.
Embodiment 6
1. write out a prescription
| Candesartan Cilexetil | 4g |
| Hydrochlorothiazide | 6.25g |
| Lactose monohydrate | 80g |
| Microcrystalline Cellulose | 30g |
| Cross-linking sodium carboxymethyl cellulose | 2.6g |
| Polyethylene glycol 6000 | 5.2g |
| Magnesium stearate | 1.3g |
| 8% Hydroxypropylcelliloxe aqueous solution | In right amount |
| Make | 1000 |
2. preparation technology
1) candesartan Cilexetil, hydrochlorothiazide are crossed 80 mesh sieves respectively, standby;
2) lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, magnesium stearate, Hydroxypropylcelliloxe are crossed 60 mesh sieves respectively, standby;
3) take by weighing candesartan Cilexetil, hydrochlorothiazide, lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and the polyethylene glycol 6000 of prescription inventory,, obtain the hybrid medicine powder by the equivalent method mix homogeneously that progressively increases;
4) get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, cross 20 mesh sieves and granulate, wet granular after 2 hours, is crossed 20 mesh sieve granulate in 60 ℃ of oven dry;
5) take by weighing the magnesium stearate of prescription inventory, join in the material behind the above-mentioned granulate, carry out always mixing, obtain described pharmaceutical composition;
6) measure drug content, it is heavy to calculate sheet, carries out tabletting with diameter 8mm punch die, control tablet hardness 5kg.
Experimental example 1
After supplementary material sieved, by following prescription mix homogeneously, get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, cross 20 mesh sieves and granulate, wet granular after 2 hours, is crossed 20 mesh sieve granulate in 60 ℃ of oven dry, compare disintegration behind the mixture tabletting, in pH6.5 phosphate buffered solution (containing 0.35% polysorbas20), detect dissolution simultaneously.The result is as shown in table 1:
Table 1:
By table 1 as seen, when the consumption of disintegrating agent cross-linking sodium carboxymethyl cellulose is lower than 2.6g when (weight ratio that accounts for recipe quantity is about 2%), the slice, thin piece disintegrate is slow, and the stripping of insoluble drug candesartan Cilexetil is relatively poor.When increasing the consumption of disintegrating agent cross-linking sodium carboxymethyl cellulose, the disintegrate of tablet and stripping improve obviously, but when consumption was higher than 5.2g, the improvement situation tended to be steady.Therefore selecting the amount ranges of cross-linking sodium carboxymethyl cellulose is the 2-4% of recipe quantity, preferred 2%.
Experimental example 2
After supplementary material sieved, by following prescription mix homogeneously, get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, cross 20 mesh sieves and granulate, wet granular after 2 hours, is crossed 20 mesh sieve granulate in 60 ℃ of oven dry, behind the mixture tabletting with the tablet that makes at 50 ℃ or 40 ℃ of storages, the line stabilization property testing of going forward side by side.It is as follows to fill a prescription, and the result is as shown in table 2:
Prescription:
| Material | Prescription 6 | Prescription 7 | Prescription 8 | Prescription 9 | Prescription 10 |
| Candesartan Cilexetil | 8g | 8g | 8g | 8g | 8g |
| Hydrochlorothiazide | 6.25g | 6.25g | 6.25g | 6.25g | 6.25g |
| Lactose monohydrate | 80g | 80g | 80g | 80g | 80g |
| Microcrystalline Cellulose | 30g | 30g | 30g | 30g | 30g |
| Cross-linking sodium carboxymethyl cellulose | 2.6g | 2.6g | 2.6g | 2.6g | 2.6g |
| Polyethylene glycol 6000 | 0.65g | 1.3g | 2.6g | 5.2g | 6.5g |
| Magnesium stearate | 1.3g | 1.3g | 1.3g | 1.3g | 1.3g |
| 8% Hydroxypropylcelliloxe aqueous solution | In right amount | In right amount | In right amount | In right amount | In right amount |
Table 2: stability test result
| Project | Prescription 6 | Prescription 7 | Prescription 8 | Prescription 9 | Prescription 10 |
| Measure initial Candesartan ester content (%) | 101.6 | 102.2 | 100.7 | 101.4 | 99.5 |
| Preserve 4 all backs candesartan Cilexetils residual (%) down for 50 ℃ | 90.4 | 93.4 | 99.5 | 99.6 | 99.8 |
| Preserve 8 all backs candesartan Cilexetils residual (%) down for 40 ℃ | 93.5 | 95.2 | 99.8 | 100.1 | 100.3 |
With each sample of making of prescription of prescription 6-10, store each specific period after, detect the content of contained active component candesartan Cilexetil in the tablet with liquid chromatography, its residual ratio is represented with percent.The amount difference of the contained stabilizing agent polyethylene glycol 6000 of prescription 6-10.From measurement result clearly as seen, the consumption of polyethylene glycol 6000 all can significantly be guaranteed the stability of principal agent candesartan Cilexetil at 2.6～6.5g (accounting for the 2%-5% of recipe quantity).For saving adjuvant, reduce production costs, the consumption of preferred polyethylene glycol 6000 is 2.6g (accounts for recipe quantity 2%), the Chinese granted patent CN 1047518C with respect to Japanese Takede Chemical Industries Ltd has reduced its consumption over half.
Claims (8)
1. a pharmaceutical composition that contains candesartan Cilexetil and hydrochlorothiazide is characterized in that, described pharmaceutical composition is made up of following prescription:
Candesartan Cilexetil 4 or 8 weight portions
Hydrochlorothiazide 6.25 weight portions
Lactose monohydrate 60～100 weight portions
Microcrystalline Cellulose 15～40 weight portions
Cross-linking sodium carboxymethyl cellulose 2.6 weight portions
Polyethylene glycol 6000 2.6 weight portions
Magnesium stearate 1.3 weight portions
8% Hydroxypropylcelliloxe aqueous solution is an amount of
2. pharmaceutical composition according to claim 1 is characterized in that, described pharmaceutical composition is a tablet.
3. pharmaceutical composition according to claim 2 is characterized in that, described tablet is to adopt following method preparation:
1) candesartan Cilexetil, hydrochlorothiazide are sieved respectively, standby;
2) lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, magnesium stearate, Hydroxypropylcelliloxe are sieved respectively, standby;
3) take by weighing the prescription inventory candesartan Cilexetil, hydrochlorothiazide, lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and polyethylene glycol 6000, mix homogeneously obtains the hybrid medicine powder;
4) get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, the granulation of sieving, after the wet granular oven dry, granulate sieves;
5) take by weighing the magnesium stearate of prescription inventory, join in the material behind the above-mentioned granulate, carry out always mixing, obtain described pharmaceutical composition;
6) resulting pharmaceutical composition is carried out tabletting.
4. claim 1 or 2 or 3 described preparation of drug combination methods is characterized in that described preparation method comprises:
1) candesartan Cilexetil, hydrochlorothiazide are sieved respectively, standby;
2) lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyethylene glycol 6000, magnesium stearate, Hydroxypropylcelliloxe are sieved respectively, standby;
3) take by weighing the prescription inventory candesartan Cilexetil, hydrochlorothiazide, lactose monohydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and polyethylene glycol 6000, mix homogeneously obtains the hybrid medicine powder;
4) get the mixed material that makes, add 8% Hydroxypropylcelliloxe aqueous solution and make soft material in right amount, the granulation of sieving, after the wet granular oven dry, granulate sieves;
5) take by weighing the magnesium stearate of prescription inventory, join in the material behind the above-mentioned granulate, carry out always mixing, obtain described pharmaceutical composition;
6) pharmaceutical composition that obtains is carried out tabletting.
5. preparation method according to claim 4 is characterized in that, sieving to crossing 80～100 mesh sieves described in the step 1).
6. preparation method according to claim 4 is characterized in that step 2) described in sieve and be to cross 60～80 mesh sieves.
7. preparation method according to claim 4 is characterized in that, the mixing described in the step is to adopt the equivalent method of progressively increasing to carry out mixing.
8. preparation method according to claim 4 is characterized in that described tabletting is that tablet hardness is controlled at 5～8kg.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102366412A (en) * | 2011-10-21 | 2012-03-07 | 四川百利药业有限责任公司 | Preparation method of tolvaptan tablet |
| CN110354086A (en) * | 2019-07-25 | 2019-10-22 | 天地恒一制药股份有限公司 | A kind of preparation method of candesartan Cilexetil tablet |
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| CN1072338A (en) * | 1991-11-20 | 1993-05-26 | 武田药品工业株式会社 | Combination of oral medication and preparation method |
| CN101623275A (en) * | 2009-03-16 | 2010-01-13 | 江苏天一时制药有限公司 | Capsule containing candesartan cilexetil and preparation method thereof |
| CN101890024A (en) * | 2009-05-18 | 2010-11-24 | 北京瑞伊人科技发展有限公司 | Candesartan cilexetil/hydrochlorothiazide composition and preparation method thereof |
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| CN1072338A (en) * | 1991-11-20 | 1993-05-26 | 武田药品工业株式会社 | Combination of oral medication and preparation method |
| CN101623275A (en) * | 2009-03-16 | 2010-01-13 | 江苏天一时制药有限公司 | Capsule containing candesartan cilexetil and preparation method thereof |
| CN101890024A (en) * | 2009-05-18 | 2010-11-24 | 北京瑞伊人科技发展有限公司 | Candesartan cilexetil/hydrochlorothiazide composition and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102366412A (en) * | 2011-10-21 | 2012-03-07 | 四川百利药业有限责任公司 | Preparation method of tolvaptan tablet |
| CN102366412B (en) * | 2011-10-21 | 2013-05-15 | 四川百利药业有限责任公司 | Preparation method of tolvaptan tablet |
| CN110354086A (en) * | 2019-07-25 | 2019-10-22 | 天地恒一制药股份有限公司 | A kind of preparation method of candesartan Cilexetil tablet |
| CN110354086B (en) * | 2019-07-25 | 2021-05-11 | 天地恒一制药股份有限公司 | Preparation method of candesartan cilexetil tablets |
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Application publication date: 20110803 |