CN114712319B - Felodipine and propranolol hydrochloride compound preparation and preparation method thereof - Google Patents

Felodipine and propranolol hydrochloride compound preparation and preparation method thereof Download PDF

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CN114712319B
CN114712319B CN202210307753.1A CN202210307753A CN114712319B CN 114712319 B CN114712319 B CN 114712319B CN 202210307753 A CN202210307753 A CN 202210307753A CN 114712319 B CN114712319 B CN 114712319B
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felodipine
propranolol hydrochloride
compound preparation
granulating
preparation
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CN114712319A (en
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陶秀梅
李婧怡
张超
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Beijing Nuokangda Pharmaceutical Technology Co ltd
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Beijing Nuokangda Pharmaceutical Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography

Abstract

The invention relates to a felodipine and propranolol hydrochloride compound preparation and a preparation method thereof. The felodipine and propranolol hydrochloride compound preparation comprises an inner layer, and the active ingredient of the compound preparation is propranolol hydrochloride; and an outer layer whose active ingredient is felodipine; the outer layer is wrapped outside the inner layer. Felodipine and propranolol hydrochloride can be combined to exert a antihypertensive effect, and propranolol hydrochloride can resist the effect of increasing the heart rate due to long-term administration of felodipine.

Description

Felodipine and propranolol hydrochloride compound preparation and preparation method thereof
Technical Field
The invention relates to a felodipine and propranolol hydrochloride compound preparation and a preparation method thereof.
Background
Along with the continuous development of related researches on hypertension, the diagnosis and treatment concepts are also continuously updated. Cardiovascular total risk treatment strategies indicate that hypertension treatment aims to minimize the total risk of cardiovascular events and death. To achieve this, therapeutic strategies include both lowering the blood pressure itself and reversing all relevant risk factors. Many large clinical trials have shown that the benefits of hypertension are mainly derived from the blood pressure reduction itself, so that the achievement of the blood pressure reduction is critical to achieve the above objective. There is growing evidence that the main determinant of risk decline is the blood pressure target value achieved by hypotensive therapy. ESH/ESC 2007 guidelines for hypertension treatment indicate: for all hypertensive patients, the target of blood pressure reduction is below 140/90mmHg, while for high risk patients (complicated with cardiovascular and cerebrovascular diseases, diabetes mellitus, renal insufficiency, etc.), the blood pressure should be reduced to at least below 130/80 mmHg. In the existing antihypertensive drugs, other 5 types of antihypertensive drugs (diuretics, beta blockers, ACEI, ARB and CCB) can be used as initial drugs and long-term maintenance drugs for antihypertensive treatment besides the lack of long-term large-scale evidence-based medical evidence of alpha receptor blockers. However, the amplitude of the depressurization in various single-drug treatments is about 10mmHg, and most patients are difficult to reach the standard. Particularly for high-risk or extremely high-risk patients, the target value of blood pressure is low and is difficult to reach. Therefore, most patients need to be treated by combining 2 or more antihypertensive drugs, which has become the mainstream strategy of the current hypertension treatment. In 2007 ESH/ESC guidelines for hypertension treatment, combination therapy with antihypertensive drugs was recommended for patients with hypertension not up to standard with single drug therapy. The individual treatment is established aiming at pharmacodynamics and pharmacological characteristics, and the combination of the antihypertensive drugs with small doses and different action mechanisms is used, so that the synergistic effect of the antihypertensive drugs can not only increase the antihypertensive effect, but also reduce the incidence rate of adverse reactions and the degree of adverse reactions. Wherein the combination of a calcium antagonist (CCB) and a beta blocker is one of the recommended regimens.
Felodipine is a long-acting dihydropyridine calcium channel antagonist that acts to reversibly compete for dihydropyridine binding sites, blocking voltage-dependent Ca in vascular smooth muscle and artificially cultured rabbit atrial cells 2+ Current and block K + Induced murine portal venous contracture. In vitro researches show that the product has stronger selective inhibition effect on vascular smooth muscle than myocardial effect; negative myotonic effects were detectable in vitro, but were not observed in whole animals. The product can reduce blood pressure due to peripheral vascular resistance, and has pharmacological effect related to dosage and increased reflex heart rate. The effect of the product on reducing the resistance of peripheral blood vessels is observed in animals and human bodies to cause mild diuretic effect. The blood pressure lowering action of the herb is dose-dependent and positively correlated with blood concentration. There may be an increase in reflex heart rate at the first week of administration, but the effect decreases over time. The heart rate may be increased by 5-10 times per minute with prolonged administration and the beta-blocker may counteract this effect.
Propranolol is a non-selective beta-adrenergic receptor blocker that competitively binds to both the β1 and β2 isoforms of adrenergic receptors. For hypertension, propranolol exerts a hypotensive effect by reducing cardiac output, inhibiting renin release and reducing vasomotor central sympathetic excitation. For angina, propranolol can reduce catecholamine or exercise-induced heart rate, systolic pressure and myocardial contraction increase, and reduce myocardial oxygen consumption. For arrhythmia, propranolol can play a role in membrane stabilization, affecting myocardial action potential.
The prior art has often selected the use of felodipine alone for the manufacture of a antihypertensive drug or the use of felodipine in combination with metoprolol succinate, which is a selective beta 1 receptor blocker that acts on the beta 1 receptor of the heart at a lower dose than it does on the beta 2 receptor on peripheral blood vessels and bronchi.
Disclosure of Invention
The present invention aims to solve at least one of the above technical problems.
The invention provides a felodipine and propranolol hydrochloride compound preparation, which comprises the following components: an inner layer, the active component of which is propranolol hydrochloride; and an outer layer whose active ingredient is felodipine; the outer layer is wrapped outside the inner layer.
According to the embodiment of the invention, the felodipine and propranolol hydrochloride compound preparation is a tablet.
According to an embodiment of the present invention, the adding auxiliary materials in the inner layer includes: and (3) a pore-forming agent and a filler.
In a further scheme, the pore-forming agent in the internal auxiliary materials can be one or more selected from polyethylene glycol, hydroxypropyl cellulose, lactose, polyvinylpyrrolidone, microcrystalline cellulose, sucrose and sodium chloride.
In a further scheme, the filler in the internal auxiliary materials can be one or more selected from starch, lactose, sucrose, dextrin, pregelatinized starch, mannitol, silicon dioxide and hydroxypropyl cellulose.
As a preferred embodiment, the inner additive in the inner layer selects hydroxypropyl cellulose to be combined with lactose to play roles of a pore-forming agent and a filler.
According to the embodiment of the invention, the internal auxiliary materials in the inner layer comprise lactose, silicon dioxide and hydroxypropyl cellulose.
According to the embodiment of the invention, the weight ratio of lactose, silicon dioxide and hydroxypropyl cellulose which are auxiliary materials added into the inner layer is (25-30): 5-20): 5, optionally (28-30): 10-20): 5, for example, 28:10:5, 30:10:5 and 28:20:5. The research shows that the hydroxypropyl cellulose and lactose are combined to play the roles of the pore-forming agent and the filler, so that the propranolol hydrochloride can be completely released, and the bioavailability is improved compared with the single use of lactose.
According to an embodiment of the invention, the lactose is anhydrous lactose.
According to the embodiment of the invention, the weight ratio of the active ingredient propranolol hydrochloride in the inner layer to the total internal auxiliary materials is 10 (38-53), for example 10:38, 10:40, 10:43, 10:45, 10:53. Researches show that the dosage of the internally added auxiliary materials can enable the propranolol to be released slowly, prevent the propranolol from being released faster in the earlier stage and reduce adverse reactions.
According to the embodiment of the invention, the weight ratio of the hydroxypropyl cellulose serving as the internal auxiliary material to lactose in the inner layer is 5 (25-30), for example 5:25, 5:28 and 5:30.
According to the embodiment of the invention, the sum of the weight of the hydroxypropyl cellulose and lactose which are added as auxiliary materials in the inner layer accounts for 45-75wt%, preferably 47-73wt% of the total weight of the inner layer.
According to an embodiment of the present invention, the additional auxiliary materials in the outer layer include: at least one or more of slow release materials, antioxidants, glidants, solubilizers, fillers and lubricants.
According to the embodiment of the invention, the slow release material can be one or more of gelatin, acacia, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, PVP (polyvinylpyrrolidone) and PEG (polyethylene glycol), and is preferably one or more of hydroxypropyl methylcellulose and hydroxypropyl cellulose.
In some embodiments, the slow release material is hydroxypropyl methylcellulose and hydroxypropyl cellulose.
In some embodiments, the hydroxypropyl methylcellulose is hypromellose (K100M) and hypromellose (E50) in a weight ratio of 10 (80-110). Specifically, for example, 10:80, 10:90, and 10:110.
In some embodiments, the slow release material comprises 56wt% to 75wt% of the weight of the outer layer.
In some embodiments, the slow release material hydroxypropyl methylcellulose (HPMC) comprises 56wt% to 75wt% of the outer layer weight.
According to the embodiment of the invention, the antioxidant can be selected from one or more of butyl-base Miao Xiang ether (BHA), dibutyl-base toluene (BHT), propyl Gallate (PG) and Tertiary Butyl Hydroquinone (TBHQ), and preferably one or two of butyl-base Miao Xiang ether (BHA) and Propyl Gallate (PG). It was found that butyl-trans-base Miao Xiang ether (BHA) or Propyl Gallate (PG) has better oxidation resistance than dibutyl-trans-base toluene (BHT). Butyl methyl Miao Xiang ether (BHA) is stable to heat, is not easy to damage under alkaline conditions, and has certain antibacterial effect and volatility.
According to the embodiment of the invention, the glidant can be one or more selected from silicon dioxide, aerosil and sodium aluminum silicate, preferably one or two of silicon dioxide and aerosil, and more preferably aerosil. The superfine silica gel powder is one kind of superfine amorphous particle with small size and in different cohesiveness and no influence on the release of the product.
According to the embodiment of the invention, the glidant can be one or two selected from silicon dioxide and micro powder silica gel. Specifically, the glidant accounts for 3 to 3.5 weight percent of the weight of the outer layer.
According to the embodiment of the invention, the solubilizer can be one or two of polyoxyethylene hydrogenated castor oil and tween, and is preferably polyoxyethylene hydrogenated castor oil with the model RH40. Specifically, the solubilizer comprises 0.01wt% to 7wt%, preferably 6.05wt% to 6.8wt% of the outer layer.
According to the embodiment of the invention, the filler can be one or more of microcrystalline cellulose, anhydrous calcium hydrophosphate, calcium hydrophosphate and mannitol.
According to an embodiment of the present invention, the lubricant may be selected from one or two of magnesium stearate and sodium stearyl fumarate.
According to an embodiment of the present invention, the additional auxiliary materials in the outer layer include: hypromellose (K100M), solubilizer (one or two of polyoxyethylene hydrogenated castor oil and tween), antioxidant (one or two of propyl gallate and butyl-warp-base Miao Xiang ether), hypromellose (E50), hypromellose, filler (one or more of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate and mannitol), glidant (one or two of silicon dioxide and micropowder silica gel) and lubricant (one or more of magnesium stearate and sodium stearyl fumarate).
According to the embodiment of the invention, the external auxiliary materials in the outer layer comprise the following components in parts by weight: 8-12 parts of hydroxypropyl methylcellulose (K100M), 8-12 parts of solubilizer (one or two of polyoxyethylene hydrogenated castor oil and tween), 0.02-0.05 part of antioxidant (one or two of propyl gallate and butyl-base Miao Xiang ether), 80-110 parts of hydroxypropyl methylcellulose (E50), 4-6 parts of hydroxypropyl cellulose, 5-40 parts of filler (one or more of microcrystalline cellulose, anhydrous calcium hydrophosphate, calcium hydrophosphate and mannitol), 4-6 parts of glidant (one or two of silicon dioxide and micro-powder silica gel) and 2-2.5 parts of lubricant (one or more of magnesium stearate and sodium stearyl fumarate). Researches show that the adopted additional auxiliary materials can ensure that propranolol hydrochloride and felodipine are released slowly, so as to achieve the synergistic effect of the drug effect.
According to the embodiment of the invention, the weight ratio of the active ingredient felodipine to all the additional auxiliary materials in the outer layer is 10 (140-155), for example 10:151. The research shows that the prescription has the characteristic of keeping the felodipine released in an extended way, can smoothly control the blood pressure and reduce the adverse reaction of the medicine.
According to the embodiment of the invention, in the felodipine and propranolol hydrochloride compound preparation, the weight ratio of felodipine to propranolol hydrochloride is 1:0.8-1.2, for example, 1:1. The research shows that the combination of the antihypertensive drugs with different action mechanisms in small doses can increase the antihypertensive effect, and simultaneously reduce the occurrence rate of adverse reactions and the degree of adverse reactions.
According to the embodiment of the invention, in the felodipine propranolol hydrochloride compound preparation, the weight ratio of the inner layer to the outer layer is (48-63) (151-165), such as 53:161. The study shows that the prescription can continuously release the medicine for a long time after the medicine is taken, so that the purpose of prolonging the medicine effect is achieved, the blood medicine concentration is stable, and the medicine taking compliance of patients is greatly improved.
According to the embodiment of the invention, the felodipine and propranolol hydrochloride compound preparation further comprises a coating layer. The coating auxiliary material can be one or more selected from carnauba wax, iron oxide reddish brown (E172), iron oxide yellow (E172), hypromellose 6mPa.s, polyethylene glycol 6000, and titanium dioxide (E171), preferably Carleno film coating premix (mark: 03F 640043-CN) or film coating premix (mark: 03F 630007-CN).
On the basis of the common knowledge in the art, the above preferred conditions can be mutually combined to obtain the preferred examples of the invention.
According to the embodiment of the invention, the felodipine and propranolol hydrochloride compound preparation is prepared as follows (weight parts):
according to the embodiment of the invention, the felodipine and propranolol hydrochloride compound preparation is prepared as follows (weight parts):
according to the felodipine and propranolol hydrochloride compound preparation, release of felodipine and propranolol hydrochloride can be reasonably controlled through a two-layer structure with the felodipine at the outer layer and propranolol hydrochloride at the inner layer, so that the treatment effect is enhanced, the frequency of taking propranolol hydrochloride is reduced, and toxic and side effects are reduced. Felodipine and propranolol hydrochloride can be combined to exert a antihypertensive effect, and propranolol hydrochloride can resist the effect of increasing the heart rate due to long-term administration of felodipine.
The invention also provides a preparation method of the felodipine and propranolol hydrochloride compound preparation, which comprises the following steps:
1) Granulating an inner layer and granulating an outer layer;
2) Granulating and tabletting the inner layer;
3) Filling part of the outer layer granulation into a die, adding the tabletting prepared in the step 2), and then adding the rest of the outer layer granulation, and tabletting.
According to the embodiment of the invention, the inner layer granulation and the outer layer granulation refer to granulating the materials of the inner layer and granulating the materials of the outer layer respectively.
According to embodiments of the present invention, granulation, such as wet granulation, may be employed by methods conventional in the art.
According to the embodiment of the invention, the inner layer granulation can be performed by adopting a 5mm flat oblique punching sheet.
According to the embodiment of the invention, the hardness of the felodipine and propranolol hydrochloride compound preparation is controlled to be 6.00-10.00kg.
In some embodiments, the inner layer granulation comprises: adding propranolol hydrochloride, pore-forming agent and filler (anhydrous lactose, hydroxypropyl cellulose and silicon dioxide) into wet granulator, stirring and mixing for 5-20min, adding wetting agent, stirring and granulating for 150s, and drying at 50deg.C.
In some embodiments, the outer granulation comprises: mixing the sustained release material with felodipine, filler, glidant, lubricant, solubilizer and antioxidant at mixing speed of 10-20rpm for 5-15min, and granulating.
In some embodiments, felodipine feedstock particle size limit D is controlled 50 ≤2μm，D 90 Less than or equal to 5 mu m. Felodipine is white to pale yellow crystals or crystalline powder, which is BCS class ii. It was found that the particle size of the starting material may affect its diffusion rate in different media, and tablets were prepared after controlling the particle size of the starting material.
In some specific examples, step 3) takes part of the outer layer particles to fill the die, adds the tablet prepared in step 2), takes the rest of the particles in step 2) to compress the tablet, and the hardness is controlled between 6.00 kg-10.00 kg-. The release of propranolol hydrochloride can be controlled after the inner layer particles are independently pressed into tablets, and the release of propranolol hydrochloride can be compared with that of propranolol hydrochloride tablets alone, so that the slow release effect of propranolol hydrochloride can be exerted.
According to the embodiment of the invention, the preparation method further comprises a step of coating after tabletting, wherein the weight of the coating can be controlled to be 3% -5%.
Specifically, the tabletting step comprises: determination of weight adoption based on intermediate product content conversionTabletting by using a shallow concave round punch, wherein the hardness is 6.00-10.00kg; the tabletting speed is 6-15 ten thousand tablets/hour. Sampling during tabletting, and detecting properties, weight difference, hardness, friability and the like.
Specifically, the coating step comprises: the coating weight gain is 3% -5%.
a. Preparing a coating liquid: the coating liquid is prepared by slowly adding the gastric-soluble film coating premix into purified water (the ratio of the coating powder to the purified water is 1:5) under the stirring state, and continuously stirring for 45min to obtain the coating liquid.
b. Preheating: the hot air temperature was set at 55℃and the drum rotation speed was 1rpm. The plain tablets are added into a coating pot for preheating, when the temperature of the product reaches 45 ℃, hot air temperature is set to 65 ℃, preheating is carried out for more than 15 minutes, and coating is started when the hot air temperature reaches 65 ℃.
c. Coating: after the preheating of the product is finished, the qualified debugging of a spray gun is confirmed, the negative pressure in a pot is between-0.01 kpa and-0.15 kpa, the rotating speed of a roller is between 2rpm and 5rpm, the atomizing air pressure is between 0.30MPa and 0.50MPa, the peristaltic pump speed is between 10rpm and 20rpm, the temperature of the product is controlled to be 40+/-5 ℃, the coating parameters and the appearance are monitored in the coating process, and the coating weight gain is controlled to be 3% -5%.
d. And (3) drying: closing the atomizing and peristaltic pump, reducing the rotating speed of the roller by 1rpm-2rpm, stopping spraying liquid, continuing to dry for 5-15min, and stopping heating. The dissolution of the drug can be slowed down by a drying process.
e. And (3) cooling: and (5) cooling the material to below 35 ℃ and discharging. The preparation process is simple and easy to operate, and is easy for mass production.
The preparation method of the felodipine and propranolol hydrochloride compound preparation is simple in process and easy for mass production.
The invention also provides a method for detecting the dissolution rate, which can predict the in-vivo dissolution behavior of the felodipine and propranolol hydrochloride compound preparation, and establish in-vivo and in-vitro correlations between in-vitro drug release (felodipine) and in-vivo drug release behavior.
The method for detecting the dissolution rate comprises the step of detecting that a sample is the felodipine and propranolol hydrochloride compound preparation; dissolution conditions: paddle + drug release device, 50rpm,500ml; the dissolution medium is acetate buffer with pH 4.0-5.5+0.2% SDS (sodium dodecyl sulfate), or water+0.2% SDS (sodium dodecyl sulfate). The dissolution rate detection method can predict in-vivo behaviors and has high resolution.
Further, the sampling time is: 1. 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, and 10h.
Further, the sampling volume was 2ml.
Further, the same volume and temperature of the dissolution medium are supplemented during liquid supplementing.
It is important to understand the relationship between in vitro and in vivo drug release behavior, which helps (1) evaluate the impact of prescription and process variable changes on product quality during the development phase; (2) predicting the performance of the commercial batch according to BE data of the declaration batch of a pilot scale; (3) facilitating the evaluation of the post-approval changes. Thus, there is a need to develop a predictive dissolution method and to establish an in vivo-in vitro correlation (IVIVR) between in vitro drug release and in vivo drug release behavior. The predictive dissolution analysis method can reasonably predict the in-vivo behaviors of medicines and distinguish prescriptions with different drug release behaviors.
Drawings
Fig. 1: examples 1, 2,3 and comparative example 2 formulation propranolol hcl in vitro and in vivo correlation curves.
Fig. 2: in vitro correlation curves of propranolol hcl in the formulations of examples 1, 5, and 6 and comparative example 4.
Fig. 3: in vitro correlation curves for felodipine in the formulations of examples 1, 7, 8 and comparative example 5.
Fig. 4: example 1 and comparative example 7 formulation felodipine in vitro correlation curves.
Fig. 5: example 1 and comparative example 8 formulation propranolol hcl correlation curves in vitro.
Fig. 6: example 1 relates to the in vitro and in vivo correlation curves of propranolol hydrochloride in the formulations of comparative example 1 and example 5.
Detailed Description
The following examples are illustrative of the invention and are not intended to limit the scope of the invention. The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase by regular vendors without the manufacturer's attention.
The particle size limit D of felodipine starting material is controlled as follows unless otherwise specified 50 ≤2μm，D 90 ≤5μm。
The coating methods used below are the same unless otherwise specified.
Example 1
The present embodiment provides a felodipine and propranolol hydrochloride compound preparation, which has the following formulation:
the preparation method comprises the following steps:
1) Granulating an inner layer: adding propranolol hydrochloride, anhydrous lactose, hydroxypropyl cellulose and silicon dioxide into a wet mixing granulator according to the granulating formula and content in the table, stirring for 10min, and adding purified water for granulating; the granules were dried at 50 ℃.
2) Granulating an outer layer: uniformly mixing hypromellose (K100M), hypromellose (E50), hypromellose, felodipine, microcrystalline cellulose, propyl gallate, silica gel micropowder and polyoxyethylene hydrogenated castor oil according to the above formula and content, adding sodium stearyl fumarate, and granulating;
3) Taking the granules in the step 1) and adopting a 5mm flat and oblique punching tablet.
4) Filling part of the granules in the step 2) into a die, adding the tablets prepared in the step 3), and then taking the rest of the granules in the step 2) to press the tablets, wherein the hardness is controlled to be 6.00-10.00kg.
5) And (5) coating.
Examples 2 to 3
The present embodiment provides a felodipine and propranolol hydrochloride compound preparation, which has the following formulation:
the preparation method comprises the following steps:
1) Granulating an inner layer: adding propranolol hydrochloride, anhydrous lactose and silicon dioxide into a wet mixing granulator according to the granulating formula and content in the table, stirring for 10min, and adding purified water for granulating; the granules were dried at 50 ℃.
2) Granulating an outer layer: uniformly mixing hypromellose (K100M), hypromellose (E50), hypromellose, felodipine, microcrystalline cellulose, propyl gallate, silica gel micropowder and polyoxyethylene hydrogenated castor oil according to the above formula and content, adding sodium stearyl fumarate, and granulating;
3) Taking the granules in the step 1) and adopting a 5mm flat and oblique punching tablet.
4) Filling part of the granules in the step 2) into a die, adding an inner layer of granules to form tablets, and then taking the rest of the granules in the step 2) to form tablets, wherein the hardness is controlled to be 6.00-10.00kg.
5) And (5) coating.
Example 4
The preparation method of the felodipine and propranolol hydrochloride compound preparation is the same as that of example 1, except that propyl gallate in the preparation is replaced by equal amount of butyl-base Miao Xiang ether.
Examples 5 to 6
The present embodiment provides a felodipine and propranolol hydrochloride compound preparation, which has the following formulation:
the preparation method comprises the following steps:
1) Granulating an inner layer: adding propranolol hydrochloride, anhydrous lactose and silicon dioxide into a wet mixing granulator according to the granulating formula and content in the table, stirring for 10min, and adding purified water for granulating; the granules were dried at 50 ℃.
2) Granulating an outer layer: uniformly mixing hypromellose (K100M), hypromellose (E50), hypromellose, felodipine, microcrystalline cellulose, propyl gallate, silica gel micropowder and polyoxyethylene hydrogenated castor oil according to the above formula and content, adding sodium stearyl fumarate, and granulating;
3) Taking the granules in the step 1) and adopting a 5mm flat and oblique punching tablet.
4) Filling part of the granules in the step 2) into a die, adding an inner layer of granules to form tablets, and then taking the rest of the granules in the step 2) to form tablets, wherein the hardness is controlled to be 6.00-10.00kg.
5) And (5) coating.
Examples 7 to 8
The present embodiment provides a felodipine and propranolol hydrochloride compound preparation, which has the following formulation:
the preparation method comprises the following steps:
1) Granulating an inner layer: adding propranolol hydrochloride, anhydrous lactose and silicon dioxide into a wet mixing granulator according to the granulating formula and content in the table, stirring for 10min, and adding purified water for granulating; the granules were dried at 50 ℃.
2) Granulating an outer layer: uniformly mixing hypromellose (K100M), hypromellose (E50), hypromellose, felodipine, microcrystalline cellulose, propyl gallate, silica gel micropowder and polyoxyethylene hydrogenated castor oil according to the above formula and content, adding sodium stearyl fumarate, and granulating;
3) Taking the granules in the step 1) and adopting a 5mm flat and oblique punching tablet.
4) Filling part of the granules in the step 2) into a die, adding an inner layer of granules to form tablets, and then taking the rest of the granules in the step 2) to form tablets, wherein the hardness is controlled to be 6.00-10.00kg.
5) And (5) coating.
Example 9
The present example provides a compound preparation of felodipine and propranolol hydrochloride, which is different from example 1 in that the silica gel micropowder in the prescription is replaced by equal amount of silica, and the preparation method is the same as that of example 1.
Comparative example 1
The comparative example 1 provides a compound preparation of felodipine and propranolol hydrochloride, no hydroxypropyl cellulose is added in the internal granulation, and the prescription is as follows:
the preparation method comprises the following steps:
1) Granulating an inner layer: adding propranolol hydrochloride, anhydrous lactose and silicon dioxide into a wet mixing granulator according to the granulating formula and content in the table, stirring for 10min, and adding purified water for granulating; the granules were dried at 50 ℃.
2) Granulating an outer layer: uniformly mixing hypromellose (K100M), hypromellose (E50), hypromellose, felodipine, microcrystalline cellulose, propyl gallate, silica gel micropowder and polyoxyethylene hydrogenated castor oil according to the above formula and content, adding sodium stearyl fumarate, and granulating;
3) Taking the granules in the step 1) and adopting a 5mm flat and oblique punching tablet.
4) Filling part of the granules in the step 2) into a die, adding an inner layer of granules to form tablets, and then taking the rest of the granules in the step 2) to form tablets, wherein the hardness is controlled to be 6.00-10.00kg.
5) And (5) coating.
Comparative example 2
This example 2 provides a compound formulation of felodipine and propranolol hydrochloride with a higher content of anhydrous lactose and a lower content of microcrystalline cellulose according to the comparative example, which is formulated as follows:
the preparation method comprises the following steps:
1) Granulating an inner layer: adding propranolol hydrochloride, anhydrous lactose, silicon dioxide and the like into a wet mixing granulator according to the granulating formula and the content in the table, stirring for 10min, and adding purified water for granulating; the granules were dried at 50 ℃.
2) Granulating an outer layer: uniformly mixing hypromellose (K100M), hypromellose (E50), hypromellose, felodipine, microcrystalline cellulose, propyl gallate, silica gel micropowder and polyoxyethylene hydrogenated castor oil according to the above formula and content, adding sodium stearyl fumarate, and granulating;
3) Taking the granules in the step 1) and adopting a 5mm flat and oblique punching tablet.
4) Filling part of the granules in the step 2) into a die, adding an inner layer of granules to form tablets, and then taking the rest of the granules in the step 2) to form tablets, wherein the hardness is controlled to be 6.00-10.00kg.
5) And (5) coating.
Comparative example 3
The preparation method of the felodipine and propranolol hydrochloride compound preparation is the same as that of example 1, except that propyl gallate in the prescription is replaced by equal amount of dibutyl-menstrual toluene.
Comparative example 4
The present embodiment provides a felodipine and propranolol hydrochloride compound preparation, wherein no silica is added in the preparation of the formulation, and the formulation is as follows:
the preparation method comprises the following steps:
1) Granulating an inner layer: adding propranolol hydrochloride, anhydrous lactose, silicon dioxide and the like into a wet mixing granulator according to the granulating formula and the content in the table, stirring for 10min, and adding purified water for granulating; the granules were dried at 50 ℃.
2) Granulating an outer layer: uniformly mixing hypromellose (K100M), hypromellose (E50), hypromellose, felodipine, microcrystalline cellulose, propyl gallate, silica gel micropowder and polyoxyethylene hydrogenated castor oil according to the above formula and content, adding sodium stearyl fumarate, and granulating;
3) Taking the granules in the step 1) and adopting a 5mm flat and oblique punching tablet.
4) Filling part of the granules in the step 2) into a die, adding an inner layer of granules to form tablets, and then taking the rest of the granules in the step 2) to form tablets, wherein the hardness is controlled to be 6.00-10.00kg.
5) And (5) coating.
Comparative example 5
The present embodiment provides a felodipine and propranolol hydrochloride compound preparation, wherein the content of hydroxypropyl cellulose in the external granulation in the prescription is higher, and the prescription is as follows:
the preparation method comprises the following steps:
1) Granulating an inner layer: adding propranolol hydrochloride, anhydrous lactose and silicon dioxide into a wet mixing granulator according to the granulating formula and content in the table, stirring for 10min, and adding purified water for granulating; the granules were dried at 50 ℃.
2) Granulating an outer layer: uniformly mixing hypromellose (K100M), hypromellose (E50), hypromellose, felodipine, microcrystalline cellulose, propyl gallate, silica gel micropowder and polyoxyethylene hydrogenated castor oil according to the above formula and content, adding sodium stearyl fumarate, and granulating;
3) Taking the granules in the step 1) and adopting a 5mm flat and oblique punching tablet.
4) Filling part of the granules in the step 2) into a die, adding an inner layer of granules to form tablets, and then taking the rest of the granules in the step 2) to form tablets, wherein the hardness is controlled to be 6.00-10.00kg.
5) And (5) coating.
Comparative example 6
The preparation method of the felodipine and propranolol hydrochloride compound preparation is the same as that of example 1, except that the superfine silica powder in the prescription is replaced by equivalent sodium aluminum silicate.
Comparative example 7
The preparation method of the felodipine and propranolol hydrochloride compound preparation is the same as that of example 1, and the preparation method is different from that of example 1 only in that the felodipine particle size in the preparation is controlled to be D90 & gt 50 mu m
Comparative example 8
This example provides propranolol hydrochloride tablets, which are formulated as follows:
granulating by conventional method, and making into tablet with hardness controlled at 6.00-10.00kg.
Comparative example 9
The formulation of felodipine and propranolol hydrochloride compound preparation is the same as that of example 1, and the preparation method is as follows: the inner and outer raw materials were directly mixed and fed into a die to compress tablets according to the prescription of example 1, and the hardness was controlled to 6.00-10.00kg.
Comparative example 10
The formulation of felodipine and propranolol hydrochloride compound preparation differs from example 1 only in that propranolol hydrochloride in the internal granulation is interchanged with felodipine in the external granulation.
Comparative example 11
The formulation of felodipine and propranolol hydrochloride compound preparation is the same as that of example 1, and the preparation method is as follows: the inner granulation was coated outside the outer granulation according to the recipe of example 1, i.e. the ingredients of the inner and outer layers of example 1 were interchanged.
The following dissolution rate detection method
Dissolution conditions: the tablet is placed in a stainless steel wire basket, the side face of the basket is welded on a stainless steel tube, and the tablet is placed in the opposite angle of the basket horizontally. The rod assembly is installed to pass through the cover of the dissolution cup and fixed to be 3.2cm away from the center of the rotating rod, the height of the basket is adjusted to be 1cm away from the upper edge of the paddle, and water is used
500ml of +0.2% SDS was used as a dissolution medium, and the rotation speed was 50rpm, and the samples were sampled at 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 8h and 10h, respectively, according to the method.
The detection method comprises the following steps:
and taking a proper amount of dissolved solution from the sample solution, filtering, and taking the subsequent filtrate.
The reference substance solution is taken to be a proper amount of felodipine reference substance, precisely weighed, added with absolute ethanol for dissolution and quantitative dilution to prepare a solution containing about 1mg of felodipine in each 1ml, precisely weighed and properly measured, quantitatively diluted with a dissolution medium to prepare a solution containing about 20 mug of felodipine in each 1ml, and uniformly shaken.
Taking a proper amount of propranolol hydrochloride reference substance, precisely weighing, adding absolute ethyl alcohol for dissolving and quantitatively diluting to prepare a solution containing about 1mg of propranolol hydrochloride in each 1ml, precisely weighing a proper amount, quantitatively diluting with a dissolution medium to prepare a solution containing about 20 mug of propranolol hydrochloride in each 1ml, and shaking uniformly.
Octadecylsilane chemically bonded silica is used as a filler under chromatographic conditions; acetonitrile-methanol-phosphate buffer (6.9 mg/ml sodium dihydrogen phosphate solution, pH value is adjusted to 3.0) by phosphoric acid (2.5:1:2) is taken as a mobile phase; the detection wavelength is 362nm; column temperature is 30 ℃; the flow rate is 1.0ml/min; the sample volume was 50. Mu.l.
The measuring method comprises precisely measuring the solution of the sample and the solution of the reference substance, injecting into a liquid chromatograph, and recording the chromatogram. The elution amount of each tablet at different times was calculated as peak area by the external standard method.
Experiment 1
The dissolution behavior of propranolol hydrochloride in the formulations of example 1 and comparative example 1 in an in vitro correlation curve is shown in the following table.
From the dissolution results, the hydroxypropyl cellulose is selected to be combined with lactose to play the roles of the pore-forming agent and the filler, so that the propranolol hydrochloride can be completely released, and the bioavailability is improved compared with the single use of lactose.
Experiment 2
The dissolution behavior of propranolol hydrochloride in the formulations of examples 1, 2 and 3 and comparative example 2 in the in vitro and in vivo correlation curves are shown in the following table and fig. 1.
The result of dissolution shows that when the total amount of the pore-foaming agent and the filler is 30mg-35mg, the pore-foaming agent and the filler are slowly released by dissolution, the total amount of the pore-foaming agent and the filler is increased to 50mg, the early release is faster, and the slow release effect is poor.
Experiment 3
Method for detecting substance
The method is based on the following steps: high performance liquid chromatography (general rule 0512 of the year 2020 edition (four parts) of Chinese pharmacopoeia)
Chromatographic column: octadecyl bonded silica gel as filler [ Waters Symmetry C (4.6X105 mm,5 μm) or equivalent chromatography column ]
Mobile phase: acetonitrile-methanol-phosphate buffer (0.08% w/V phosphoric acid and 0.8% w/V sodium dihydrogen phosphate dihydrate solution) (2:1:2)
Detection wavelength: 254nm
Flow rate: 1.0ml/min
Column temperature: 30 DEG C
Preparing a solution:
solvent: acetonitrile-methanol-phosphate buffer (0.08% w/V phosphoric acid and 0.8% w/V sodium dihydrogen phosphate dihydrate solution) (2:1:2).
System applicability solution: and taking proper amounts of felodipine and an impurity A reference substance, adding a mobile phase for dissolution and dilution to prepare mixed solutions which respectively contain about 0.2mg and 4 mug in each 1ml, and taking the mixed solutions as a system applicability solution.
Control solution: taking a proper amount of felodipine impurity A reference substance, precisely weighing, adding a mobile phase for dissolution, and quantitatively diluting to prepare a solution containing about 4 mug per 1ml serving as a reference substance solution.
Test solution: taking 10 pieces of the product, placing the product into a 500ml measuring flask, adding 200ml of acetonitrile, carrying out ultrasonic treatment for 20 minutes, adding 100ml of methanol, mechanically shaking for 30 minutes to dissolve felodipine, cooling to room temperature, diluting to a scale with phosphate buffer solution, shaking uniformly, centrifuging, taking supernatant, filtering with a polytetrafluoroethylene membrane, and taking the subsequent filtrate as a sample solution.
Control solution: a proper amount of the sample solution was precisely measured, and the solution was quantitatively diluted with a mobile phase to prepare a solution containing about 0.4. Mu.g per 1ml as a control solution.
Judgment standard:
taking 20 μl of the system applicability solution, and injecting into a liquid chromatograph, wherein the separation degree between the impurity A peak and the felodipine peak is more than 3.0. And then precisely measuring 20 mu l of each of the control solution, the control solution and the test solution, respectively injecting into a liquid chromatograph, recording a chromatogram till the retention time of a main peak is 3 times, wherein the chromatogram of the test solution has impurity peaks, the impurity A is calculated according to an external standard method and is not more than 2.0 percent in terms of peak area, the peak area of other single impurities is not more than the main peak area (0.2 percent) of the control solution, and the total impurity amount is not more than 3.0 percent.
Impurity A, impurity B and impurity C are respectively dehydrofelodipine, 4- (2 ',3' -dichlorophenyl) -2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid dimethyl ester and 4- (2, 3-dichlorophenyl) -2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxylic acid diethyl ester.
Examples 1,4 and comparative example 3 the formulations were exposed to high temperatures of 60 c and the relevant material growth is shown in the table below.
The experimental result of influencing factors shows that the invention adopts butyl-base Miao Xiang ether (BHA) or propyl gallate for sample preparation, and the sample preparation is placed at the high temperature of 60 ℃ for 10 days, and the impurity is slightly increased but the increase amplitude is obviously smaller than that of dibutyl-base toluene (BHT), thus indicating that the product has stable property.
Experiment 4
The dissolution behavior of propranolol hydrochloride in the formulations of examples 1, 5, 6 and comparative example 4 in the in vitro correlation curve is shown in the following table and fig. 2.
According to the dissolution result, when the addition amount of the silicon dioxide is 5mg-20mg, the silicon dioxide is slowly released, the use amount of the silicon dioxide added into the silicon dioxide is reduced, the earlier release is slowed down, the release amount of the silicon dioxide in the first 2 hours is smaller, and the bioavailability is lower.
Experiment 5
The dissolution behavior of felodipine in the formulations of examples 1, 7, 8 and comparative example 5 in the in vitro correlation curve is shown in the following table and fig. 3.
The dissolution result shows that when the dosage of the slow-release material ranges from 90mg to 120mg, the slow-release material is slowly released, the dosage of the slow-release material is reduced, the early-stage release is faster, and the slow-release effect is poorer.
Experiment 6
In examples 1 and 9, compared with comparative example 6, silica fume, and sodium aluminum silicate were used as glidants, and the control results of the tabletting process are shown in the following table.
Tabletting process control Example 1 Example 9 Comparative example 6
Hardness (N) 40-60 40-60 10-30
Friability (%) 0.17 0.14 0.84
As can be seen from the tabletting control result, the sodium aluminum silicate is selected for sample preparation, the sample has poor compressibility, low hardness and poor friability, and the silicon dioxide and the micro silica gel are selected for sample preparation, so that the sample has good compressibility, high hardness and good friability, and is convenient for subsequent coating and transportation.
Experiment 7
The dissolution behavior of felodipine in the formulations of example 1 and comparative example 7 in the in vitro correlation curve is shown in the following table and fig. 4.
The dissolution result shows that the particle size of the selected felodipine is larger than 50 mu m, the dissolution platform is 70, and the bioavailability is poor.
Experiment 8
The dissolution behavior of propranolol hydrochloride in the formulations of example 1 and comparative example 8 in an in vitro correlation curve is shown in the following table and fig. 5.
Compared with a single preparation, the compound preparation prepared by the invention has the advantages that the dissolution achieves a slow release effect, and the compound preparation can act synergistically with felodipine to resist the effect of increasing the heart rate due to long-term administration of felodipine.
Experiment 9
The dissolution behavior of the propranolol hydrochloride in the formulations of example 1 and comparative example 1 and example 5 in the in vitro correlation curves is shown in the following table and fig. 6.
Example 1 and comparative example 1, example 5 were subjected to experimental BE studies in 12 healthy subjects, and random, single dose, double crossover studies were performed to compare example/contrast ratio in vivo consistency, with reference to "guidelines for study of human bioequivalence of chemical drug imitative drugs study with pharmacokinetic parameters as end point evaluation index".
Summary of PK parameters
The results show that under the condition that the in vitro dissolution curves are greatly different, the in vivo Cmax and the in vivo AUC are greatly different, so that the selected curves of felodipine and propranolol hydrochloride have the strongest in vivo and in vitro correlation.
Experiment 10
Example 1 dissolution behavior of propranolol hydrochloride and felodipine in the formulation of comparative example 9 in an in vitro-in vivo correlation curve:
as can be seen from the dissolution results, compared with the preparation prepared by directly mixing the inner layer raw material and the outer layer raw material and filling the mixture into a die to be pressed into a tablet, the preparation prepared by the internal and external double-layer granulating process has the advantages of slow release effect, sustained release after administration, long-time sustained release of the medicine to achieve the purpose of prolonging the medicine effect and stable blood concentration.
Experiment 11
Example 1 dissolution behavior of propranolol hydrochloride and felodipine in the formulation of comparative example 10 in an in vitro-in vivo correlation curve:
as shown by the dissolution results, compared with the externally added and granulated felodipine exchangeable preparation, the external granulating process for granulating the inner layer of the propranolol has the advantages that the dissolution of the propranolol hydrochloride achieves a slow release effect, the medicine can be continuously released for a long time after the medicine is taken, the purpose of prolonging the medicine effect is achieved, the blood concentration is stable, and the slow release effect of the felodipine is not obviously influenced.
Experiment 12
Example 1 and comparative example 11 formulation of propranolol hydrochloride, felodipine dissolved in an in vitro-in correlation curve:
as shown by the dissolution results, compared with the preparation prepared by granulating the inner layer granulating and coating the outer layer granulating, the preparation prepared by granulating the inner layer granulating and coating the outer layer granulating has the advantages that the dissolution of propranolol hydrochloride and felodipine achieves a slow-release effect, and the medicine can be continuously released for a long time after the medicine is taken so as to achieve the purpose of prolonging the medicine effect, and the blood concentration is stable.
While the invention has been described in detail in the foregoing general description and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that modifications and improvements can be made thereto. Accordingly, such modifications or improvements may be made without departing from the spirit of the invention and are intended to be within the scope of the invention as claimed.

Claims (6)

1. The felodipine and propranolol hydrochloride compound preparation is characterized in that the felodipine and propranolol hydrochloride compound preparation is a tablet; the compound preparation comprises the following components:
an inner layer, the active component of which is propranolol hydrochloride; a kind of electronic device with high-pressure air-conditioning system
An outer layer, the active ingredient of which is felodipine; the outer layer is wrapped outside the inner layer;
the felodipine and propranolol hydrochloride compound preparation is prepared as follows:
；
controlling the particle size limit D of felodipine raw material 50 ≤2μm，D 90 ≤5μm；
The preparation method of the felodipine and propranolol hydrochloride compound preparation comprises the following steps:
1) Granulating an inner layer and granulating an outer layer;
2) Granulating and tabletting the inner layer;
3) Filling part of the outer layer granulation into a die, adding the tabletting prepared in the step 2), and then adding the rest of the outer layer granulation, and tabletting.
2. The compound preparation of felodipine and propranolol hydrochloride according to claim 1, wherein the weight ratio of felodipine to propranolol hydrochloride in the compound preparation of felodipine and propranolol hydrochloride is 1:1; and/or the number of the groups of groups,
in the felodipine and propranolol hydrochloride compound preparation, the weight ratio of the inner layer to the outer layer is 53:161.
3. The compound preparation of felodipine and propranolol hydrochloride according to claim 1 or 2, further comprising a coating layer.
4. The felodipine and propranolol hydrochloride compound preparation according to claim 3, wherein the coating auxiliary materials of the coating layer are selected from one or more of carnauba wax, iron oxide reddish brown E172, iron oxide yellow E172, hypromellose 6mPa.s, polyethylene glycol 6000 and titanium dioxide E171.
5. The compound preparation of felodipine and propranolol hydrochloride according to claim 3, wherein the coating auxiliary material of the coating layer is a film coating premix.
6. The preparation method of the felodipine and propranolol hydrochloride compound preparation according to any one of claims 1 to 5, which is characterized by comprising the following steps:
1) Granulating an inner layer and granulating an outer layer;
2) Granulating and tabletting the inner layer;
3) Filling part of the outer layer granulation into a die, adding the tabletting prepared in the step 2), and then adding the rest of the outer layer granulation, and tabletting.
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