CN115105477A - Medicinal composition containing irbesartan and amlodipine and preparation method thereof - Google Patents
Medicinal composition containing irbesartan and amlodipine and preparation method thereof Download PDFInfo
- Publication number
- CN115105477A CN115105477A CN202210713753.1A CN202210713753A CN115105477A CN 115105477 A CN115105477 A CN 115105477A CN 202210713753 A CN202210713753 A CN 202210713753A CN 115105477 A CN115105477 A CN 115105477A
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- CN
- China
- Prior art keywords
- irbesartan
- amlodipine
- tablet
- binder
- coating material
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000002947 C09CA04 - Irbesartan Substances 0.000 claims abstract description 71
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 claims abstract description 71
- 229960002198 irbesartan Drugs 0.000 claims abstract description 71
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Images
Classifications
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
The invention relates to a medicinal composition containing irbesartan and amlodipine and a preparation method thereof. In the composition, irbesartan and amlodipine are physically separated, the particle size distribution D90 of irbesartan is less than or equal to 100 mu m, and the dosage form is a tablet; the composition further comprises at least a binder which is polyvinyl alcohol and has a viscosity of 4.0 to 20.0mPa · s at 20 ℃ and a concentration of 2 to 10% in the case of a binder solution. The method comprises the following steps: irbesartan is treated; mixing the processed irbesartan, the filler and part of the disintegrant to obtain a uniform dry mixture, and then adding an adhesive for granulation; drying and granulating; adding amlodipine and the disintegrant with the rest prescription amount, mixing uniformly, and then adding the lubricant for total mixing; tabletting; and (4) coating. The invention realizes the rapid dissolution of irbesartan and the good stability of amlodipine; the process is simple and is particularly suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations; in particular, the present invention relates to a pharmaceutical composition containing irbesartan and amlodipine and a preparation method thereof.
Background
Irbesartan is a potent orally active selective angiotensin ii receptor (AT1 type) antagonist. The antagonist has selective antagonistic effect, and can increase blood plasma renin level and angiotensin II level and reduce blood plasma aldosterone concentration, and has blood pressure lowering effect. The usual dosage of the antagonist is 50 to 300 mg.
Amlodipine is a dihydropyridine calcium antagonist (also called calcium antagonist or slow channel blocker), can inhibit calcium ions from entering vascular smooth muscle and cardiac muscle through membrane, belongs to peripheral arterial vasodilator, and directly acts on the vascular smooth muscle, thereby reducing peripheral vascular resistance and blood pressure. Amlodipine is commonly used pharmaceutically in its besylate, maleate or mesylate form, particularly as a besylate salt, with common dosages of amlodipine being 2.5mg, 5mg or 10 mg.
The combined use of an angiotensin II receptor antagonist and a calcium ion antagonist is a combination recommended by worldwide guidelines for the treatment of hypertension. The combination of the long-acting irbesartan and the long-acting amlodipine can improve the antihypertensive effect and the medication compliance.
Irbesartan is almost insoluble in water, has a parabolic pH-solubility curve in aqueous media, has a minimum solubility between pH 2.0 and 6.0, and has a maximum solubility in 0.1N HCl and pH 7.5 phosphate buffer. Due to its extremely low water solubility, it is challenging to make small size tablets by adding limited excipients to facilitate their wetting, disintegration and achieve rapid release; moreover, because of its relatively low bulk and tap densities, it is also prone to electrostatic agglomeration and strong adhesion, making it difficult to prepare effective doses of the drug into small-sized tablets of uniform weight and hardness.
Amlodipine besylate has a relatively low bulk and tap density, exhibits poor flowability, and occupies a small proportion of the total tablet weight, further causing problems such as tableting or uniformity of dosage units. WO 2006/059217 discloses that amlodipine causes degradation in a humid hot environment, one of the main routes of degradation is via catalytic oxidation, which is pH dependent, yielding one of the known main degradation products as impurity D, and thus is not suitable for wet granulation.
Japanese patent JP2011207873A discloses a pharmaceutical composition containing irbesartan and amlodipine or a salt thereof, which is obtained by: the preparation method comprises the steps of adopting a wet granulation process to perform wet granulation on irbesartan and part of medicinal excipients separately, drying, blending the granulated irbesartan and amlodipine, and preparing tablets.
Chinese patent CN102573804A discloses a fixed dose solid pharmaceutical composition comprising irbesartan and amlodipine besylate, which is obtained by three ways: embedding irbesartan in the form of coated granules in an extragranular matrix comprising amlodipine besylate, wherein irbesartan is granulated with a binder such as HPMC and amlodipine is added in the extragranular portion before the tableting step; respectively granulating irbesartan and amlodipine by using respective proper adhesives, then blending the granules with a lubricant and tabletting; ③ irbesartan granules and amlodipine granules each containing an excipient are separated by an inert layer, and the solid composition takes the form of a three-layer tablet.
Chinese patent CN103860511B discloses a pharmaceutical composition containing irbesartan and amlodipine besylate and a preparation method thereof, uses irbesartan, amlodipine besylate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, aerosil, magnesium stearate and coating material as the formula, through a dry granulation and tabletting process, the irbesartan and the amlodipine besylate which are crushed and sieved are mixed with microcrystalline cellulose, croscarmellose sodium, aerosil and a part of magnesium stearate, dry granulation is carried out, then mixing with the rest magnesium stearate, tabletting and coating to make the product have good disintegration property, which is helpful for improving the dissolution rate of the medicine, the method overcomes the defects of a wet granulation process, is simple in production process, high in production efficiency, suitable for industrial large-scale production, and good in content uniformity and stability. According to the preparation method, the dry granulation process is adopted, so that the risk that the impurity D (namely the impurity I collected under the item of amlodipine besylate in the second part of Chinese pharmacopoeia) is increased due to exposure of amlodipine to a damp and hot condition is avoided, but the preparation method can clearly see that the effective physical isolation condition can not be created for irbesartan and amlodipine.
Chinese patent CN 108578404B discloses a pharmaceutical composition containing irbesartan and amlodipine and a preparation method thereof, in order to provide a stable pharmaceutical composition containing irbesartan and amlodipine, wherein irbesartan and amlodipine are completed by fluidized bed one-step mixing, granulating and drying processes. However, a blend of irbesartan and aerosil and a blend of amlodipine and microcrystalline cellulose need to be prepared in advance respectively, and then fluidized bed granulation is carried out together with sieved mannitol and half amount of disintegrant; the process is complex and not beneficial to industrial production. In addition, aerosil is used in the composition of the invention in order to sieve with irbesartan to make a blend. However, aerosil is a very fine (particle size of about 15nm), lightweight and loose powder which is difficult to pass freely through a screen due to its too light weight and often undergoes adsorption; moreover, inhalation of the dust can cause respiratory tract irritation, which is not good for the health of operators. The binder used in this patent is polyvinyl alcohol as in japanese patent JP2011207873A and is preferably used in the composition in an amount ranging from 1.0% to 3.0%, preferably 2.0%, but no grade of polyvinyl alcohol is taught or suggested at all.
Polyvinyl alcohol (PVA) is a water-soluble synthetic polymer containing both hydrophilic and hydrophobic groups in the molecule. There are various grades of polyvinyl alcohol available on the market, and the degree of polymerization and the degree of alcoholysis are two major factors determining the physical properties. The structure of polyvinyl alcohol is as follows:
the medicinal grade polyvinyl alcohol is partially alcoholyzed and is named according to a coding system, a first group of figures after the trade name represents the approximate kinetic viscosity (mPa & s) of a 4% (W/V) polyvinyl alcohol aqueous solution at 20 ℃, a second group of figures represents the alcoholysis degree, and different grades of polyvinyl alcohol have different viscosities.
In the book of handbook of pharmaceutical adjuvants, it can be used as coating agent, lubricant, solubilizer and viscosity enhancer. In the pharmaceutical preparation or preparation process, it is mainly used for topical application and ophthalmic preparation, and also used for oral sustained release preparation and transdermal patch. Polyvinyl alcohol is commonly used for moisture barrier coating of tablets because of its very good gas barrier effect. However, in the existing oral solid preparations, polyvinyl alcohol is rarely and hardly thought to be used as a binder for granulation, and is often used as a film-forming material in a coating agent.
As known to those skilled in the art, irbesartan is a BCS 2 drug, namely a low-dissolution high-permeability drug, and dissolution is a key factor influencing in vivo absorption, but the irbesartan is relatively stable. Amlodipine is BCS 1 or 3, belongs to high-solubility high-permeability medicines or high-solubility low-permeability medicines, and dissolution is not a key factor influencing in vivo absorption, but the product has poor stability and is sensitive to damp and heat, so that the content of impurity D is increased. Therefore, aiming at the defects in the prior art, the pharmaceutical composition containing irbesartan and amlodipine needs to be provided, and the irbesartan can be quickly dissolved out, and simultaneously, the amlodipine has good stability.
Disclosure of Invention
In order to solve the technical problems, the invention provides the following technical scheme:
in one aspect, the present invention provides a pharmaceutical composition comprising irbesartan and amlodipine, wherein irbesartan and amlodipine are physically separated.
According to a preferred embodiment of the present invention, wherein amlodipine is amlodipine besylate, the dosage form of the pharmaceutical composition is a tablet; in the tablet, the amount of irbesartan is 75 mg/tablet to 150 mg/tablet, preferably 100 mg/tablet, and the amount of amlodipine besylate is 5 mg/tablet or 10 mg/tablet in terms of amlodipine.
According to a preferred embodiment of the invention, the dosage form comprises a core and a film coat surrounding the core, the core is a single-layer sheet-like structure, the film coat is made of a gastric soluble film coating material, the gastric soluble film coating material is composed of a film forming material, a plasticizer and a coloring agent, the film forming material comprises hypromellose, hyprolose and polyvinyl alcohol, the plasticizer comprises polyethylene glycol, propylene glycol, glycerol and an opacifier, the opacifier comprises titanium dioxide, and the coloring agent comprises yellow iron oxide and red iron oxide.
According to a preferred embodiment of the invention, the pharmaceutical composition further comprises excipients comprising a filler, a binder, a disintegrant, a lubricant and a coating material, wherein the binder is polyvinyl alcohol selected from polyvinyl alcohol p-88, wherein p is a positive integer and 1. ltoreq. p.ltoreq.20, the viscosity of the binder at 20 ℃ is 4.0 to 20.0 mPa.s, preferably 4.0 to 10.0 mPa.s, when the binder is a binder solution, the concentration of the binder solution is 2 to 10% (W/W), preferably 4 to 8% (W/W), the solvent in the binder solution is water, or an aqueous solution containing 0 to 20% (W/W) ethanol, preferably water, the amount of the binder is 2 to 5 mg/tablet; the filler comprises mannitol, microcrystalline cellulose, sorbitol, lactose, pregelatinized starch, corn starch, preferably mannitol, microcrystalline cellulose, and the amount of filler is 40-60 mg/tablet; the disintegrant comprises croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, corn starch, microcrystalline cellulose, sodium carboxymethylcellulose, preferably croscarmellose sodium, and the amount of disintegrant is 5-15 mg/tablet; the lubricant comprises magnesium stearate, hard sodium fumarate, hydrogenated vegetable oil, polyvinyl alcohol, pulvis Talci, preferably magnesium stearate, and the amount of lubricant is 1-5 mg/tablet; the coating material is film coating material, preferably gastric soluble film coating material, and the amount of the coating material is 1-10 mg/tablet.
According to a preferred embodiment of the present invention, wherein the particle size distribution D90 of irbesartan is 100 μm or less, preferably D90 is 60 μm or less, the particle size distribution is measured according to the light scattering method described in the "Chinese pharmacopoeia", 2020 edition.
In another aspect, the present invention provides a method for preparing the above pharmaceutical composition comprising irbesartan and amlodipine, comprising the steps of:
(1) irbesartan is pretreated to control the particle size distribution D90 of irbesartan to be less than or equal to 100 mu m, and the particle size distribution is measured according to a light scattering method recorded in 'Chinese pharmacopoeia' 2020 edition;
(2) mixing irbesartan, a filling agent and part of disintegrating agent pretreated in the step (1) to obtain a uniform dry mixture, and then adding a binding agent into the dry mixture to granulate to obtain wet granules;
(3) drying the wet granulate to control moisture, and then pelletizing to obtain dry granulate;
(4) adding amlodipine and the rest prescription amount of disintegrant to the dry granules to be uniformly mixed, and then adding a lubricant to the dry granules to be subjected to total mixing to obtain total mixed granules;
(5) tabletting the total mixed granules to obtain tablet cores;
(6) the tablet core is coated with a coating material to obtain a film-coated tablet in which irbesartan and amlodipine are physically separated.
According to another preferred embodiment of the present invention, wherein the pre-treatment comprises crushing and sieving; the binder is polyvinyl alcohol selected from polyvinyl alcohol p-88, wherein p is a positive integer and 1 ≦ p ≦ 20, the viscosity of the binder at 20 ℃ is 4.0 to 20.0mPa · s, preferably 4.0 to 10.0mPa · s, when the binder is a binder solution, the concentration of the binder solution is 2 to 10% (W/W), preferably 4 to 8% (W/W), the solvent in the binder solution is water, or an ethanol-water solution containing 0 to 20% (W/W), preferably water; drying the wet granules to control the water content to be less than or equal to 2 percent.
According to another preferred embodiment of the present invention, wherein the filler comprises mannitol, microcrystalline cellulose, sorbitol, lactose, pregelatinized starch, corn starch, preferably mannitol, microcrystalline cellulose, the disintegrant comprises croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, corn starch, microcrystalline cellulose, sodium carboxymethylcellulose, preferably croscarmellose sodium, the lubricant comprises magnesium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, polyvinyl alcohol, talc, preferably magnesium stearate, and the coating material is a film coating material, preferably a gastric-soluble film coating material.
According to another preferred embodiment of the present invention, wherein amlodipine is amlodipine besylate, irbesartan has a particle size distribution D90 ≤ 60 μm, and the core is a monolayer sheet-like structure.
According to another preferred embodiment of the present invention, wherein in the film coated tablet, the amount of irbesartan is 75 mg/tablet to 150 mg/tablet, preferably 100 mg/tablet, and the amount of amlodipine besylate is 5 mg/tablet or 10 mg/tablet in terms of amlodipine; the amount of the binder is 2 to 5 mg/tablet, the amount of the filler is 40 to 60 mg/tablet, the total amount of the disintegrant is 5 to 15 mg/tablet, the amount of the lubricant is 1 to 5 mg/tablet, and the amount of the coating material is 1 to 10 mg/tablet.
Compared with the prior art, the method has simple process and is particularly suitable for industrial production. Moreover, the invention realizes the good stability of amlodipine while realizing the quick dissolution of irbesartan.
Drawings
The present invention is described below with reference to the accompanying drawings, but the present invention is not limited thereto. In the drawings:
FIG. 1 shows the dissolution profile of irbesartan in 0.1mol/L hydrochloric acid solution, wherein the conditions in 0.1mol/L hydrochloric acid solution are dissolution conditions without differentiating forces.
Figure 2 shows the dissolution profile of irbesartan in phosphate buffer pH 6.8.
Detailed Description
In order that the invention may be more clearly understood, the invention will now be described in detail by way of preferred embodiments and with reference to the accompanying drawings, but the invention is not limited thereto in any way.
It is to be noted that the scientific terms and test methods mentioned in the present invention, which are not explained or detailed, have the same meanings and contents as understood by those skilled in the art.
In addition, the numerical ranges in the present invention include the endpoints and any point value between the endpoints. For example, the range of values 1 to 10 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; the numerical range of 0.1-0.9 comprises 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 and 0.9; the numerical range of 0.01-0.09 comprises 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08 and 0.09; the numerical range of 0.08-0.21 includes 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20 and 0.21. In the present invention, "above", "below" and "within" include the number, and "above/above", "below/less than" and "insufficient" do not include the number.
The term "coating" used in the present invention refers to a multifunctional protective layer which is formed by coating sugar or other film-forming materials on the outer surface of a pharmaceutical solid preparation and can be tightly adhered after drying, and is one of the most important links of modern pharmaceutical technology.
The term "coating material" used in the present invention refers to sugar or other film forming material required in the coating process, which mainly has control, sustained release, controlled sustained release, gastric dissolution, enteric solubility, protection, etc. on the functions generated by the drug solid preparation. The coating materials can be divided into gastric-soluble coating materials and enteric-soluble coating materials according to the action part. The gastric-soluble coating material is also called water-soluble coating material, and is soluble in gastric juice or water, and the main material types include acrylic resin IV, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (povidone, PVP), polyvinyl acetal diethylaminoacetate (AEA), and the like. The enteric coating material is a coating material which is not decomposed in gastric juice and is dissolved after entering the intestinal tract, and the main material types of the enteric coating material are acrylic resin I, II and III, Cellulose Acetate Phthalate (CAP), cellulose acetate phthalate (cellulose acetate phthalate, CAP), hypromellose phthalate (HPMCP), polyvinyl alcohol acetate phthalate (PVAP) and the like.
The term "core" as used herein refers to the portion of the coated tablet from which the coating film is removed.
The term "film coat" used in the present invention means that a layer of relatively stable polymer material is coated on the core of the tablet, and the film coat is named because the film layer is relatively thin. The coating material is mainly divided into the gastric-soluble coating material, the enteric-soluble coating material and the water-insoluble coating material, wherein the water-insoluble coating material is a high-molecular film coating material which is insoluble in water, and the main material types are ethyl cellulose and cellulose acetate.
According to some embodiments of the present invention, there is provided a pharmaceutical composition comprising irbesartan and amlodipine besylate, wherein irbesartan and amlodipine besylate are physically separated. Preferably, the pharmaceutical composition provided by the invention consists of irbesartan, amlodipine besylate and excipient, and the dosage form is a tablet.
According to some embodiments of the invention, the dosage form of the invention consists of a core and a film coat, the core being in the form of a single layer tablet, which is then film coated with a gastric soluble film coating material. Wherein, the content of irbesartan in the tablet of the invention is 75mg to 150mg, preferably 100 mg; amlodipine is amlodipine besylate, and the amount in the tablet is 5mg or 10mg (calculated as amlodipine).
Preferably, in the present invention, the particle size distribution D90 of irbesartan is controlled to be less than or equal to 100 μm, preferably D90 is controlled to be less than or equal to 60 μm, and the determination method comprises the light scattering method recorded in the fourth part of the Chinese pharmacopoeia of the current edition.
According to some embodiments of the invention, the excipient of the invention comprises a filler, a binder, a disintegrant, a lubricant, and a coating material.
According to some embodiments of the invention, the adhesive of the invention is polyvinyl alcohol, having a viscosity of 4.0 to 20.0 mPa-s [ 4% (W/V) dynamic viscosity of aqueous solution, 20 ℃ ], preferably 4.0 to 10.0 mPa-s; the concentration of the prepared adhesive solution is 2-10% (W/W), preferably 4-8% (W/W), and the solvent is water or 0-20% (W/W) ethanol-water solution, preferably water.
According to some embodiments of the present invention, there is provided a method for preparing a pharmaceutical composition containing irbesartan and amlodipine, comprising the steps of:
(1) crushing or screening irbesartan to control the particle size distribution D90 of irbesartan to be less than or equal to 100 microns, preferably D90 to be less than or equal to 60 microns;
(2) mixing irbesartan, a filling agent and part of disintegrating agent pretreated in the step (1) to obtain a uniform dry mixture, and then adding a binding agent into the dry mixture to granulate to obtain wet granules;
(3) drying the wet granulate to control moisture, preferably less than or equal to 2%, and then granulating to obtain dry granulate;
(4) adding amlodipine and the rest prescription amount of disintegrating agent into the dry granules to be uniformly mixed, and then adding a lubricant into the dry granules to be subjected to total mixing to obtain total mixed granules;
(5) tabletting the total mixed granules to obtain tablet cores;
(6) the tablet core is coated with a coating material to obtain a film-coated tablet in which irbesartan and amlodipine are physically separated.
Preferably, the pre-treatment comprises crushing and sieving.
Preferably, the binder is polyvinyl alcohol selected from polyvinyl alcohol p-88, where p is a positive integer, and 1. ltoreq. p.ltoreq.20 (available from Merck KGaA), the viscosity of the binder at 20 ℃ is 4.0 to 20.0 mPa.s, preferably 4.0 to 10.0 mPa.s, when the binder is a binder solution, the concentration of the binder solution is 2 to 10% (W/W), preferably 4 to 8% (W/W), the solvent in the binder solution is water, or an ethanol-water solution containing 0 to 20% (W/W), preferably water, e.g. purified water.
In the invention, the filler comprises mannitol, microcrystalline cellulose, sorbitol, lactose, pregelatinized starch and corn starch; the disintegrating agent comprises croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, corn starch, microcrystalline cellulose, and carboxymethylcellulose sodium; the lubricant comprises magnesium stearate, hard sodium fumarate, hydrogenated vegetable oil, polyvinyl alcohol, and pulvis Talci; the coating material comprises a film coating material. Preferably, the filler comprises mannitol and microcrystalline cellulose, the disintegrant comprises croscarmellose sodium, the lubricant comprises magnesium stearate, and the coating material is a gastric-soluble film coating material.
In some embodiments of the invention, the amlodipine is amlodipine besylate and the core is a monolayer sheet-like structure.
In some embodiments of the invention the amount of irbesartan is 75 mg/tablet to 150 mg/tablet, preferably 100 mg/tablet and the amount of amlodipine besylate is 5 mg/tablet or 10 mg/tablet calculated as amlodipine, in said film coated tablet.
According to certain preferred embodiments of the present invention, there is provided a method for preparing a pharmaceutical composition containing irbesartan and amlodipine, comprising the steps of:
(1) crushing or screening irbesartan to control the particle size distribution D90 of irbesartan to be less than or equal to 60 mu m;
(2) putting the irbesartan, mannitol, microcrystalline cellulose and part of croscarmellose sodium pretreated in the step (1) into a wet granulator for mixing to obtain a uniform dry mixture, and then adding an adhesive solution for granulation to obtain wet granules;
(3) drying the wet granules to control the moisture content to be less than or equal to 2%, and then finishing the granules to obtain dry granules;
(4) adding amlodipine besylate and the rest of the cross-linked sodium carboxymethyl cellulose in the prescription amount into the dry granules to be uniformly mixed, and then adding magnesium stearate into the dry granules to be subjected to total mixing to obtain total mixed granules;
(5) tabletting the total mixed granules to obtain tablet cores;
(6) coating the tablet core by adopting a gastric-soluble film coating material to obtain a film coated tablet in which irbesartan and amlodipine are physically separated.
For those skilled in the art, the present invention performs only wet granulation of irbesartan since amlodipine is sensitive to heat and humidity to cause the increase of the major degradation impurity D. On one hand, the problems of low density and easy agglomeration of irbesartan per se are solved, and the wettability of irbesartan is improved, so that the dissolution rate is improved; on the other hand, after irbesartan and excipient are granulated by using an adhesive solution, the adhesive polyvinyl alcohol has excellent film forming property, and irbesartan is coated after particles are dried to achieve physical isolation from amlodipine, so that good stability of amlodipine is realized. As a result of extensive and intensive studies, the present inventors have unexpectedly found that the particle size of irbesartan, the viscosity of polyvinyl alcohol, and the concentration of a formulated adhesive solution are key factors affecting the dissolution of irbesartan and the stabilization of amlodipine, and that achieving a good balance among the particle size of irbesartan, the viscosity of polyvinyl alcohol, and the concentration of an adhesive formulation solution can accomplish the present invention. No teaching or suggestion is given in the prior art, which is unpredictable and unexpected for a person skilled in the art.
In the medicinal composition, the Irbesartan controls the particle size distribution D90 to be less than or equal to 100 microns, preferably D90 to be less than or equal to 60 microns, and the smaller particle size is favorable for improving the dissolution rate of the medicament and creates conditions for quick dissolution of the medicament. Surprisingly and unexpectedly, to achieve the objects of the present invention, the viscosity of the polyvinyl alcohol and the concentration when used as a binder are particularly defined, wherein the viscosity of the polyvinyl alcohol is from 4.0 to 20.0 mPas [ 4% (W/V) dynamic viscosity of aqueous solution, 20 ℃ ], preferably from 4.0 to 10.0 mPas. It is formulated to a concentration of 2 to 10% (W/W), preferably 4 to 8% (W/W) in the binder solution. Accordingly, the invention meets the requirement of irbesartan on quick dissolution and also has good stability of amlodipine, which is beyond the range expected by the technical personnel in the field. When the concentration of the binder solution is more than 10% (W/W), the solubility of polyvinyl alcohol in the solution is significantly limited to result in an unfavorably prolonged dissolution time course, which is not suitable for industrial production, thereby failing to achieve the advantageous effects of the present invention; when the concentration of the binder solution is less than 2% (W/W), the need to add a large amount of solvent results in an unfavorable extension of the drying time course, which is disadvantageous for physical isolation between irbesartan and amlodipine, and an extension of the process operation time and an increase in energy consumption are disadvantageous for industrial production.
The preparation method of the medicinal composition adopts a wet granulation process, uses a polyvinyl alcohol solution as an adhesive to wrap irbesartan and part of excipients in granules, and forms physical isolation with amlodipine outside the granules, thereby realizing better stability of the amlodipine. In addition, in the present invention, the pharmaceutical composition is in the form of a film-coated tablet.
Compared with the prior art, the method has simple process, becomes standard process operation on a tablet production line in an oral solid preparation workshop, and is particularly suitable for industrial production. Surprisingly and unexpectedly, the present invention achieves good stability of amlodipine while achieving rapid dissolution of irbesartan by controlling a good balance among particle size of irbesartan, viscosity of polyvinyl alcohol, and concentration of binder solution.
Apparatus and method for particle size distribution determination：
The instrument comprises: BT-9300LD laser particle size analyzer (from Dandong Baite Instrument Co., Ltd.)
The method comprises the following steps: wet method measurement in light scattering method
Dispersing agent: isopar G (alias "odorless solvent oil")
Circulation speed: 1200rpm
Ultrasonic time: 0s
Light-shielding rate: between 10% and 20%
Optical mode: mie
Analysis mode: general purpose
Examples
The invention will now be described with reference to examples. The following examples are illustrative only and are not to be construed as limiting the spirit, spirit and scope of the invention.
Examples 1 to 3 below representThe inventionExamples 4 to 6 showComparison ofAnd (4) preparing the preparation.
Example 1
Prescription:
the preparation method comprises the following steps:
step (1): irbesartan (from Huahai pharmaceutical industry Co., Ltd., Zhejiang) was pulverized, and its particle size was measured by a wet method using a laser particle size analyzer (from Dandong Baite instruments Co., Ltd., BT-9300LD) with a particle size D90 of 41.1 μm for use.
Step (2): polyvinyl alcohol 4-88(Merck KGaA) is placed in purified water (self-made) and stirred to be completely dissolved, and the polyvinyl alcohol is heated at 90 ℃ for 5min during stirring to accelerate the dissolution of the polyvinyl alcohol, so that an adhesive solution (with the concentration of 4%, W/W) is obtained for later use.
And (3): irbesartan (from Zhejiang Huahai pharmaceutical Co., Ltd.), mannitol (from Guangxi Nanning chemical pharmaceuticals Co., Ltd.), microcrystalline cellulose (from Asahi Kasei Chemicals Corporation), croscarmellose sodium (from JRS Pharma GmbH & Co. KG.) (internal addition) were placed in a wet mixing granulator (from Shenzhen Xinyite technology Co., Ltd., model: G6) to mix for 5min, and the above binder solution was added to granulate.
And (4): the wet granules were dried in a fluidized bed (model: WBF-1G, from Chongqing Engel granulation coating technology Co., Ltd.) with an inlet air temperature of 60 ℃ and a dry granule moisture of 2% or less. Then, the granules were sized with a 1.0mm sieve (from Shenzhen, believer technologies, Ltd.).
And (5): the granulated granules were mixed with amlodipine besylate (from Changzhou Riming pharmaceutical industry Co., Ltd.) and croscarmellose sodium (from JRS Pharma GmbH & Co. KG.) (plus) for 10min, and magnesium stearate (from Anhui mountain river pharmaceutic adjuvants Co., Ltd.) was added thereto and mixed for 5 min.
And (6): the total blended granulation was tabletted.
And (7): the tablet cores were coated with a high-efficiency coating machine (model: Labcoating II, from Shenzhen Xinyite technologies, Inc.).
Example 2
Prescription:
the preparation method comprises the following steps:
example 2 was prepared according to a similar preparation to example 1.
Example 3
Prescription:
the preparation method comprises the following steps:
example 3 was prepared according to a similar preparation to example 1.
(comparative) example 4
Prescription:
the recipe of example 4 was the same as that of example 1.
The preparation method comprises the following steps:
the other steps of example 4 are the same as the corresponding steps of example 1 except for the difference in irbesartan treatment manner under step (1) of the preparation method of example 1. Irbesartan in example 4 was not pulverized and its particle size D90 was found to be 204.8. mu.m.
(comparative) example 5
Prescription:
the preparation method comprises the following steps:
example 5 was prepared according to a similar preparation to example 1.
(comparative) example 6
Prescription:
the preparation method comprises the following steps:
example 6 was prepared according to a similar preparation to example 1.
Dissolution analysis
The samples prepared in examples 1 to 6 above were mixed with a commercial product name of japan using a chinese pharmacopoeia paddle method apparatus at a rotation speed of 50 rpm:
combination tables, Specifications: 100mg/5mg, manufacturer: the dissolution curves of irbesartan fractions in 0.1mol/L hydrochloric acid solution and pH 6.8 phosphate buffer were examined together by Sumitomo pharmaceutical Co. The results are shown in FIGS. 1 and 2, wherein FIG. 1 shows a comparison of dissolution curves of the sample in a 0.1mol/L hydrochloric acid solution, and FIG. 2 shows a comparison of dissolution curves of the sample in a pH 6.8 phosphate buffer.
As is clear from FIG. 1, although the dissolution of the samples of examples 4 to 5 was slightly slower in the first 15min than in examples 1 to 3 and 6, both satisfied 15min > 85%, and the dissolution curves were similar to those of the Japanese commercial products
Similarly, the medium has no distinguishing force on the in-vitro dissolution of the irbesartan, and the difference of prescription change cannot be effectively distinguished, which is related to the fact that the irbesartan has higher solubility in a 0.1mol/L hydrochloric acid solution medium. However, as can be seen from fig. 2, when phosphate buffer at pH 6.8 is used as an dissolution medium, the change in the dissolution of irbesartan due to the change in particle size, viscosity and concentration of the binder can be effectively distinguished. Example 4 sample irbesartan, without crushing, showed the slowest dissolution curve and is comparable to that of marketed products in Japan
Are not similar; examples 5 and 6 samples polyvinyl alcohol viscosity > 20 mPas, the greater the viscosity, the slower the dissolution, the dissolution profile and the Japanese market
Are not similar; to pairIn the samples of examples 1-3, irbesartan was pulverized, the particle size D90 was controlled to be 60 μm or less, the viscosity of polyvinyl alcohol was controlled to be 4-20 mPas, the binder concentration was controlled to be 4-8% (W/W), and the dissolution curves were similar to those of the Japanese commercial products
Similarly.
Stability study
The 100mg/5mg gauge samples of examples 1-6 above and the film-coated tablets in the original package of the Japanese marketed product were packaged in high density polyethylene bottles and subjected to an accelerated test under 40 ℃/75% RH for 6 months to detect irbesartan impurity I and amlodipine impurity D. The results are shown in Table 1 below.
TABLE 1 stability results
As can be seen from the results of table 1 above, the increase levels of irbesartan impurity i and amlodipine impurity D in the samples of examples 1 to 6 are comparable to those of the japanese marketed drugs. In particular, as can be seen from comparison between example 1 and example 4, the irbesartan bulk drug grinding operation does not affect the quality of the bulk drug, and shows good stability. The invention improves the stability of amlodipine by reducing the exposure between irbesartan and amlodipine, so as to realize good medicine quality.
Example 7
Prescription:
the formulation of example 7 was the same as that of example 1 except that 86.4 mg/tablet of purified water as a solvent was replaced with a mixed solvent consisting of 8.64 mg/tablet of ethanol and 77.76 mg/tablet of purified water, i.e., a 10% (W/W) ethanol-water solution as a solvent.
The preparation method comprises the following steps:
the experimental procedure of example 7 was the same as that of example 1.
The final dissolution analysis results and stability study results were similar to example 1, and example 7 achieved the technical effect of the present invention.
(comparative) example 8
Prescription:
the formulation of example 8 was the same as that of example 1 except that 86.4 mg/tablet of solvent purified water was replaced with 196.4 mg/tablet of solvent purified water.
The preparation method comprises the following steps:
the experimental procedure of example 8 was the same as that of example 1.
The experimental result shows that physical isolation between irbesartan and amlodipine cannot be realized, the process operation time of the process is too long, the energy consumption is too large, industrial production cannot be implemented, and dissolution analysis and stability research cannot be carried out.
(comparative) example 9
Prescription:
the formulation of example 9 was the same as that of example 1 except that 86.4 mg/tablet of purified water was replaced with 30.69 mg/tablet of purified water as the solvent.
The preparation method comprises the following steps:
the experimental procedure of example 9 was the same as that of example 1.
Experimental results show that in the process, the dissolution of the polyvinyl alcohol in the aqueous solution is excessively limited, so that the dissolution time course is obviously prolonged, industrial production cannot be implemented, and dissolution analysis and stability research cannot be carried out.
The invention has been described above by way of preferred embodiments and specific examples. However, various modifications, adaptations, variations, and alternatives to the embodiments and examples of the present invention may be made without departing from the spirit and scope of the invention. Also, various modifications, adaptations, variations and alterations of the embodiments of the present invention do not affect the scope of the claims of the present invention, but rather fall within the scope of the claims of the present invention.
Claims (10)
1. A pharmaceutical composition comprising irbesartan and amlodipine, wherein irbesartan and amlodipine are physically separated.
2. The pharmaceutical composition comprising irbesartan and amlodipine according to claim 1, wherein amlodipine is amlodipine besylate, and the dosage form of the pharmaceutical composition is a tablet; in the tablet, the amount of irbesartan is 75 mg/tablet to 150 mg/tablet, preferably 100 mg/tablet, and the amount of amlodipine besylate is 5 mg/tablet or 10 mg/tablet in terms of amlodipine.
3. The pharmaceutical composition containing irbesartan and amlodipine according to claim 2, wherein the dosage form comprises a core and a film coating surrounding the core, the core is a single-layer sheet-like structure, the film coating is made of a gastric soluble film coating material consisting of a film forming material comprising hypromellose, hyprolose, polyvinyl alcohol, a plasticizer comprising polyethylene glycol, propylene glycol, glycerin, an opacifier comprising titanium dioxide, and a colorant comprising ferric oxide yellow and ferric oxide red.
4. The pharmaceutical composition containing irbesartan and amlodipine according to claim 1, further comprising excipients including a filler, a binder, a disintegrant, a lubricant and a coating material, wherein the binder is polyvinyl alcohol selected from polyvinyl alcohol p-88, wherein p is a positive integer, and 1 ≦ p ≦ 20, the binder has a viscosity of 4.0 to 20.0 mPa-s, preferably 4.0 to 10.0 mPa-s at 20 ℃, when the binder is a binder solution having a concentration of 2 to 10% (W/W), preferably 4 to 8% (W/W), the solvent in the binder solution is water, or an ethanol-water solution containing 0 to 20% (W/W), preferably water, the amount of the binder is 2 to 5 mg/tablet; the filler comprises mannitol, microcrystalline cellulose, sorbitol, lactose, pregelatinized starch and corn starch, preferably mannitol and microcrystalline cellulose, and the amount of the filler is 40-60 mg/tablet; the disintegrant comprises croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, corn starch, microcrystalline cellulose and sodium carboxymethylcellulose, preferably croscarmellose sodium, and the amount of the disintegrant is 5-15 mg/tablet; the lubricant comprises magnesium stearate, sodium fumarate, hydrogenated vegetable oil, polyvinyl alcohol and talcum powder, preferably magnesium stearate, and the amount of the lubricant is 1-5 mg/tablet; the coating material is a film coating material, preferably a gastric soluble film coating material, and the amount of the coating material is 1 to 10 mg/tablet.
5. The pharmaceutical composition containing irbesartan and amlodipine according to any one of claims 1 to 4, wherein irbesartan has a particle size distribution D90 ≤ 100 μ ι η, preferably D90 ≤ 60 μ ι η, measured according to a light scattering method described in the "Chinese pharmacopoeia", 2020 edition.
6. A process for preparing the pharmaceutical composition containing irbesartan and amlodipine according to any one of claims 1 to 5, comprising the steps of:
(1) irbesartan is pretreated to control the particle size distribution D90 of irbesartan to be less than or equal to 100 mu m, wherein the particle size distribution is measured according to a light scattering method recorded in 'Chinese pharmacopoeia' 2020 edition;
(2) mixing irbesartan, a filling agent and part of disintegrating agent pretreated in the step (1) to obtain a uniform dry mixture, and then adding a binding agent into the dry mixture to granulate to obtain wet granules;
(3) drying the wet granulation to control moisture and then size grading to obtain dry granulation;
(4) adding amlodipine and the rest of the prescribed amount of disintegrant to the dry granules to mix them uniformly, and then adding a lubricant thereto to carry out total mixing to obtain total mixed granules;
(5) tabletting the total blended granules to obtain tablet cores;
(6) and coating the tablet core with a coating material to obtain a film-coated tablet in which irbesartan and amlodipine are physically separated.
7. The method of claim 6, wherein the pre-treatment comprises crushing and sieving; the binder is a polyvinyl alcohol selected from the group consisting of polyvinyl alcohol p-88, wherein p is a positive integer, and 1 ≦ p ≦ 20, the binder having a viscosity at 20 ℃ of 4.0 to 20.0mPa · s, preferably 4.0 to 10.0mPa · s, the concentration of the binder solution being 2 to 10% (W/W), preferably 4 to 8% (W/W), when the binder is a binder solution, the solvent in which is water, or an ethanol-water solution containing 0 to 20% (W/W), preferably water; drying the wet granules to control the water content to be less than or equal to 2 percent.
8. The method according to claim 6, wherein the filler comprises mannitol, microcrystalline cellulose, sorbitol, lactose, pregelatinized starch, corn starch, preferably mannitol, microcrystalline cellulose, the disintegrant comprises croscarmellose sodium, crospovidone, low substituted hydroxypropylcellulose, corn starch, microcrystalline cellulose, sodium carboxymethylcellulose, preferably croscarmellose sodium, the lubricant comprises magnesium stearate, sodium hard fumarate, hydrogenated vegetable oil, polyvinyl alcohol, talc, preferably magnesium stearate, and the coating material is a film coating material, preferably a gastric soluble film coating material.
9. The method according to claim 6, wherein amlodipine is amlodipine besylate, irbesartan has a particle size distribution D90 ≤ 60 μm, and the core is a monolayer sheet-like structure.
10. The method according to claim 9, wherein the amount of irbesartan in the film coated tablet is 75 mg/tablet to 150 mg/tablet, preferably 100 mg/tablet, and the amount of amlodipine besylate is 5 mg/tablet or 10 mg/tablet calculated as amlodipine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2011207873A (en) * | 2010-03-10 | 2011-10-20 | Dainippon Sumitomo Pharma Co Ltd | Pharmaceutical composition containing irbesartan and amlodipine or salt of the same |
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Application publication date: 20220927 |