CN114010632A - Enalapril maleate and furosemide compound tablet and preparation method and application thereof - Google Patents
Enalapril maleate and furosemide compound tablet and preparation method and application thereof Download PDFInfo
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- CN114010632A CN114010632A CN202111514843.XA CN202111514843A CN114010632A CN 114010632 A CN114010632 A CN 114010632A CN 202111514843 A CN202111514843 A CN 202111514843A CN 114010632 A CN114010632 A CN 114010632A
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- Prior art keywords
- enalapril maleate
- furosemide
- medicine
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- gas
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract
The invention provides enalapril maleate and furosemide compound tablets and a preparation method and application thereof, the compound tablets comprise enalapril maleate medicine-containing layers, furosemide medicine-containing layers and blank isolating layers positioned in the middle, the mixed materials of the enalapril maleate medicine-containing layers comprise enalapril maleate coated particles/powder, the mixed materials of the blank isolating layers comprise a filling agent, a disintegrating agent and a lubricating agent, and the mixed materials of the furosemide medicine-containing layers comprise furosemide and auxiliary materials; mixing the mixture of enalapril maleate medicine-containing layer, the mixture of the blank isolating layer and the mixture of furosemide medicine-containing layer in turn, and tabletting; the compound tablet adopts a multilayer tablet preparation form, so that two incompatible medicinal components are compounded and separated, the compound tablet is convenient to use clinically, the quality stability of the product can be ensured, the content and impurities do not have obvious change after long-term storage, and the stability of the product and the convenience of clinical use can be ensured.
Description
Technical Field
The invention belongs to the technical field of animal treatment, and particularly relates to a fixed-dose combined multilayer tablet of enalapril maleate and furosemide with stable quality, and a preparation method and application of the product.
Background
With the increasing living standard of people, the family pet feeding is gradually popularized. Statistically, the number of domestic pet dogs in 2019 is close to 8000 ten thousand. With the increasing number of pet dogs, the incidence of heart failure in dogs has been on the rise in recent years. Heart failure is a systemic blood circulation disorder disease accompanied by weakened myocardial contractility, reduced blood output of the heart and insufficient blood supply of the arterial system, which has serious influence on dogs and great threat to the lives of dogs.
Heart failure in dogs is further classified into acute heart failure and chronic heart failure. The causes of acute heart failure include sudden massive exercise, too fast or large amount of infusion during intravenous drip, exceeding the heart load, injection of drugs with strong stimulation to the cardiac muscle, and direct attack of viruses and toxins on the cardiac muscle during some infectious diseases such as canine distemper, poisoning and fever, which causes secondary acute heart failure. The causes of chronic heart failure include a long-term massive exercise, and the chronic heart failure is also commonly caused by pericarditis, myocarditis, endocarditis, emphysema and the like.
Enalapril maleate, having the chemical name of N- [ (S) -1- (ethoxycarbonyl) -3-phenylpropyl ] -L-alanyl-L-proline maleate, has the following structural formula:
enalapril maleate is an angiotensin converting enzyme inhibitor drug which is marketed second after captopril, is taken as a prodrug and is rapidly hydrolyzed in liver to form active diacid metabolite enalaprilat after oral administration to exert the angiotensin converting enzyme inhibitor effect, so that angiotensin I can not be converted into angiotensin II, thereby causing the relaxation of blood vessels of the whole body, finally achieving the effect of reducing blood pressure, effectively treating congestive heart failure, and having obvious blood pressure reducing effect on II-renal hypertension, I-renal hypertension and spontaneous hypertension rat models. In the field of pet therapy, enalapril maleate is mainly used for treating mild, moderate or severe congestive heart failure in dogs due to mitral regurgitation or dilated cardiomyopathy. For improving exercise tolerance and survival in dogs with mild, moderate or severe congestive heart failure.
Furosemide, chemical name 2- [ (2-furylmethyl) amino ] -5- (sulfamoyl) -4-chlorobenzoic acid. The structural formula is as follows:
furosemide has strong and short diuretic action and is a powerful diuretic. Furosemide mainly acts on the medulla part of the ascending branch of renal tubule loop to inhibit Cl-And Na+The reabsorption of (2) also acts on the cortex of ascending branches. The result is lumen fluid Na+、Cl-Increased concentration of Na in the medullary interstitial fluid+、Cl-The concentration is reduced, and the concentration function of renal tubules is reduced, thereby causing water and Na+、Cl-Excretion is increased. Due to Na+Reduced reabsorption, distal convoluted tubules Na+Increasing the concentration of Na+-K+And Na+-H+Increase in exchange to K+、H+Excretion is increased. In addition, furosemide can inhibit Na pairing of proximal and distal convoluted tubules+、Cl-Reabsorption of (A) causing distal convoluted tubules Na+-K+Exchange enhancement, promotion of K+The excretion of (1). Furosemide is mainly used for treating edema caused by heart, liver, kidney and other diseases, especially for the case that other diuretics are not effective; can be used for treating acute pulmonary edema, cerebral edema, acute renal failure and hypertension; can promote by combining with fluid infusionAnd (4) excretion of toxic substances.
Veterinary and pet owners readily understand that oral administration of medications to pets is very challenging, and providing a method that simplifies medication administration to pet patients can ensure that treatment is reliably provided, and can optimize the quality of life of the pet if the pet owner and the pet experience are positive.
Thus, the inclusion of two core recommended therapies in a single dosage form for treating heart failure in dogs would be of great benefit, as it would allow for more convenient administration and would reduce the number of tablets, which would improve the compliance of the veterinary regimen.
However, when combining two active agents in one single dosage form, there is a possibility of interaction between the two active ingredients and between the active and inactive ingredients, and furthermore, the two active ingredients may have different degradation characteristics, resulting in chemical stability problems of the final dosage form.
Enalapril maleate raw material is very stable per se, but is particularly susceptible to degradation in the formulation, especially when the excipients are acidic or basic. In an acidic environment, the main degradation product is enalapril diketone, and in an alkaline environment, the main degradation product is enalaprilat. According to the report, the common auxiliary materials used in the existing tablet, such as magnesium stearate, microcrystalline cellulose, calcium (hydrogen) phosphate, starch, carboxymethyl starch sodium crospovidone, croscarmellose sodium and the like, can accelerate the degradation of enalapril. To solve the problem of storage stability of enalapril maleate tablets, various patents have been published. U.S. patent 5,562,921 discloses the addition of sodium bicarbonate as a stabilizer to the formulation, while replacing magnesium stearate with zinc stearate as a lubricant; WO98/26765 and WO01/19348 teach the use of maleic acid as a stabilizer in the formulation in a certain proportion; CN102357084A says that the stability of enalapril maleate in tablets can be improved by adding malic acid and tartaric acid. However, the effect is not ideal on the whole, and the problem in the production of enalapril maleate tablets cannot be solved. Research data shows that in products on the market, the proportion of unqualified products containing related substances in 1-2 years after production can reach 70%, and the proportion of unqualified products containing related substances in 2-3 years after production is as high as nearly 90%, so that the degradation within the shelf life exceeds the standard, and the degradation of enalapril maleate tablets still remains a ubiquitous problem, and the problem restricts the quality of the existing enalapril maleate tablet products and cannot ensure safe clinical use and long-term storage.
The chemical structure of furosemide contains carboxylic acid and sulfamoyl, and the furosemide is acidic and basic, and is not compatible with enalapril maleate in nature. Therefore, combining the two pharmaceutical ingredients in a fixed dosage form is a technical challenge.
Therefore, there is a need to improve the prior art and to provide a novel stable enalapril maleate and furosemide combination dosage form.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide an enalapril maleate and furosemide compound tablet with stable quality, a preparation method and application thereof.
In order to achieve the above purpose, the solution of the invention is as follows:
the invention provides an enalapril maleate and furosemide compound tablet, which comprises an enalapril maleate medicine containing layer, a blank isolating layer and a furosemide medicine containing layer, wherein the blank isolating layer is positioned between the enalapril maleate medicine containing layer and the furosemide medicine containing layer.
Wherein the mixed material of the enalapril maleate medicine-containing layer comprises enalapril maleate coated particles/powder.
The mixture of the blank isolating layer comprises a filling agent, a disintegrating agent and a lubricating agent.
The mixed material of the furosemide medicine-containing layer comprises furosemide and auxiliary materials.
As a preferred embodiment of the invention, the enalapril maleate coated particles/powder comprise enalapril maleate and a low-melting auxiliary material in a mass ratio of 1:10-1: 20.
In a preferred embodiment of the present invention, the low melting point auxiliary material is one or more selected from glyceryl behenate, glyceryl monostearate, glyceryl distearate, polyoxyethylene hydrogenated castor oil, glyceryl monolinoleate and solid polyethylene glycol.
As a preferred embodiment of the present invention, the enalapril maleate-coated granules/powder further include other auxiliary materials including a filler and a lubricant.
As a preferred embodiment of the invention, the filler is direct compression lactose.
As a preferred embodiment of the present invention, the lubricant is one or more selected from glyceryl behenate and hydrogenated castor oil.
In a preferred embodiment of the present invention, the filler in the mixture of the blank isolation layer is selected from one or more of direct compression lactose, microcrystalline cellulose and pregelatinized starch.
As a preferred embodiment of the present invention, the disintegrant in the mixture of the blank isolation layer is selected from more than one of croscarmellose sodium, crospovidone, and sodium starch glycolate.
As a preferred embodiment of the present invention, the lubricant in the mixed material of the blank isolation layer is more than one selected from glyceryl behenate, hydrogenated castor oil and stearic acid.
In a preferred embodiment of the invention, the auxiliary materials in the mixed material of the furosemide medicine-containing layer comprise a filler, a disintegrant, a binder, a glidant and a lubricant.
In a preferred embodiment of the present invention, the filler is one or more selected from the group consisting of microcrystalline cellulose, lactose and pregelatinized starch.
As a preferred embodiment of the present invention, the disintegrant is one or more selected from croscarmellose sodium, crospovidone, sodium starch glycolate, and pregelatinized starch.
As a preferred embodiment of the present invention, the binder is selected from one or more of povidone and hydroxypropylmethyl cellulose.
As a preferred embodiment of the invention, the glidant is silicon dioxide.
As a preferred embodiment of the present invention, the lubricant is one or more selected from glyceryl behenate and hydrogenated castor oil.
The second aspect of the present invention provides a method for preparing the enalapril maleate and furosemide compound tablet, which comprises the following steps:
(1) and preparing a mixed material of the enalapril maleate medicine-containing layer: heating and melting the auxiliary materials with low melting point, adding enalapril maleate powder, stirring and mixing to obtain enalapril maleate-coated particles/powder; mixing the enalapril maleate coated particles/powder with other auxiliary materials to obtain a mixed material of the enalapril maleate drug-containing layer;
(2) and preparing a mixed material of the blank isolation layer: mixing the filler, the disintegrant and the lubricant to obtain a mixed material of the blank isolation layer;
(3) and preparing a mixed material of the furosemide medicine-containing layer: mixing furosemide, a filling agent and a disintegrating agent, performing wet granulation by using an adhesive, adding a flow aid and a lubricant, and uniformly mixing to obtain a mixed material of the furosemide medicine-containing layer;
(4) sequentially adding the mixture of the enalapril maleate medicine-containing layer, the mixture of the blank isolating layer and the mixture of the furosemide medicine-containing layer into a hopper for mixing, and tabletting to obtain the enalapril maleate and furosemide compound tablet.
The third purpose of the invention is to provide the application of the enalapril maleate and furosemide maleate compound tablet in preparing the medicine for treating the heart failure of the pet, which is mainly used for treating the congestive heart failure of the dog and is easy to use, thereby improving the compliance and the treatment effect of veterinarians and pet owners.
Due to the adoption of the scheme, the invention has the beneficial effects that:
the enalapril maleate and furosemide compound tablet adopts a multilayer tablet preparation form, so that two incompatible medicine components are compounded and separated, the clinical use is convenient, the stable product quality can be ensured, the content and impurities have no obvious change after long-term storage, the stability of the product can be ensured, and the clinical use convenience can also be ensured; enalapril maleate is wrapped inside the low-melting-point auxiliary material, so that oxygen and moisture can be isolated, and the stability of enalapril maleate is greatly improved. In addition, the preparation process is simple and the production cost is low.
Drawings
FIG. 1 is a graph showing the change in acceleration test of enalaprilat in examples of the present invention, comparative examples and standards.
FIG. 2 is a graph showing the change in acceleration test of enalapril dione in examples of the present invention, comparative examples and standards.
FIG. 3 is a graph showing the change in accelerated test of other monomers in examples of the present invention, comparative examples and standards.
FIG. 4 is a graph showing the change of total impurities in accelerated tests in examples of the present invention, comparative examples and standards.
FIG. 5 is a graph showing the change in the long-term test of enalaprilat in examples of the present invention, comparative examples and standards.
FIG. 6 is a graph showing the change of enalapril dione in a long-term test in examples of the present invention, comparative examples and standards.
FIG. 7 is a graph showing the change in the long-term test of other monomers in examples of the present invention, comparative examples and standards.
FIG. 8 is a graph showing the change of total impurities in the long-term test in examples of the present invention, comparative examples and standards.
Detailed Description
The invention provides enalapril maleate and furosemide maleate compound tablets and a preparation method and application thereof.
< Enalapril maleate and furosemide compound tablet >
The enalapril maleate and furosemide compound tablet adopts a multilayer tablet form and comprises an enalapril maleate medicine containing layer, a blank isolating layer and a furosemide medicine containing layer, wherein the blank isolating layer is positioned between the enalapril maleate medicine containing layer and the furosemide medicine containing layer, namely, the enalapril maleate and the furosemide exist in different tablet layers respectively, and the blank isolating layer is sandwiched between the enalapril maleate medicine containing layer and the furosemide medicine containing layer.
Wherein, the enalapril maleate and the furosemide contained in the compound enalapril maleate tablet and the furosemide tablet are combined in a fixed dose of 1: 10.
(Enalapril maleate medicinal layer)
The mixed material of the drug-containing layer of enalapril maleate comprises granules/powder wrapped by enalapril maleate and other auxiliary materials.
Specifically, the enalapril maleate coated particles/powder comprise enalapril maleate and low-melting auxiliary materials (actually, enalapril maleate is in the form of low-melting auxiliary material coated particles/powder), and the mass ratio is 1:10-1: 20.
The low melting point adjuvant is selected from more than one of glyceryl behenate, glyceryl monostearate, glyceryl distearate, polyoxyethylene hydrogenated castor oil, glyceryl monolinoleate or solid polyethylene glycol (PEG), and the PEG is selected from more than one of PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 6000 and PEG 8000.
The other auxiliary materials in the enalapril maleate medicine-containing layer are common auxiliary materials, including a filling agent and a lubricating agent. Wherein the bulking agent is lactose under direct pressure, and lactose under direct pressure is commercially available, such as available from MEIKO
Or
The lubricant is more than one selected from glyceryl behenate and hydrogenated castor oil.
(blank isolation layer)
The blank isolation layer contains no medicine and is composed of blank auxiliary materials. The mixture of the blank isolating layer comprises a filling agent, a disintegrating agent and a lubricating agent.
Wherein the filler is selected from one or more of direct compression lactose, microcrystalline cellulose and pregelatinized starch, and the microcrystalline cellulose is selected from microcrystalline cellulose 101, microcrystalline cellulose 102, microcrystalline cellulose 103, microcrystalline cellulose 301, microcrystalline cellulose 302, and microcrystallineOne or more of cellulose 12, microcrystalline cellulose 14, microcrystalline cellulose 200, and microcrystalline cellulose 112. Direct compression of lactose as a product of Mei-Ding le Co
Or
The disintegrant is selected from more than one of croscarmellose sodium, crospovidone and carboxymethyl starch sodium (CMS-Na).
The lubricant is selected from more than one of glyceryl behenate, hydrogenated castor oil and stearic acid.
(Furosemide drug-containing layer)
The mixed material of the furosemide medicine-containing layer comprises furosemide and auxiliary materials, wherein the furosemide is in a granular form.
Wherein the auxiliary materials comprise a filling agent, a disintegrating agent, an adhesive, a glidant and a lubricant.
Specifically, the filler is one or more selected from microcrystalline cellulose, lactose and pregelatinized starch, and the microcrystalline cellulose is microcrystalline cellulose 101.
The disintegrant is selected from more than one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch (CMS-Na) and pregelatinized starch.
The binder is selected from one or more of polyvidone (PVP) and hydroxypropyl methylcellulose, wherein the hydroxypropyl methylcellulose is selected from one or more of hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E30, hydroxypropyl methylcellulose E50 and hydroxypropyl methylcellulose E100. The polyvidone is at least one selected from PVP-k30 and PVP-k 90.
The glidant is silicon dioxide.
The lubricant is more than one selected from glyceryl behenate and hydrogenated castor oil.
< preparation method of enalapril maleate and furosemide compound tablet >
The preparation method of the enalapril maleate and furosemide compound tablet comprises the following steps:
(1) and preparing a mixed material of the enalapril maleate medicine-containing layer: heating and melting the low-melting-point auxiliary materials, adding enalapril maleate powder, and uniformly stirring and mixing. Then the mixture is prepared into granules/powder by a hot-melt spray cooling granulation device. The melting medicine suspension is conveyed to a two-fluid air-flow type spray gun by a barrel double screw of the hot melting spray cooling granulation equipment, and then is atomized into fog drops by compressed air, and the fog drops are fully contacted with air frozen at ultralow temperature for instant cold solidification. And part of condensed particles are settled into a collecting barrel at the bottom of the drying chamber along with the air flow, and the tail gas is subjected to secondary gas-solid separation by a dust removal device to collect the product. The obtained granules are collected by a screen mesh to obtain granules of 30-100 meshes, and the granules/powder are coated with enalapril maleate. The enalapril maleate in the granules prepared by the method is wrapped in the auxiliary materials with low melting points (namely the enalapril maleate wrapped granules/powder), so that oxygen and moisture can be isolated, and the stability of the enalapril maleate is greatly improved. Then, uniformly mixing the enalapril maleate-coated particles/powder with other auxiliary materials at room temperature to obtain a first layer of mixed material;
(2) and preparing a mixed material of the blank isolation layer: adopting a direct mixing and tabletting process, and directly and uniformly mixing the filler, the disintegrant and the lubricant to obtain a mixed material of the blank isolation layer, namely the mixed material of the second layer;
(3) and preparing a mixed material of the furosemide medicine-containing layer: uniformly mixing the furosemide, the filling agent and the disintegrating agent, then carrying out wet granulation by using an adhesive, then adding the flow aid and the lubricant, and uniformly mixing to obtain a mixed material of the furosemide medicine-containing layer, namely the mixed material of the third layer;
(4) and on a rotary tablet press for pressing multilayer tablets, sequentially adding the mixed material of the enalapril maleate medicine-containing layer into a first hopper clockwise, adjusting the machine filling until the required weight is reached, then adding the mixed material of a blank isolating layer into a second hopper, carrying out the same operation until the required weight is obtained, then adding the mixed material of the furosemide medicine-containing layer into a third hopper, carrying out the same operation until the required weight is obtained, and finally pressing the three layers of materials to form a multilayer tablet to obtain the enalapril maleate and furosemide compound tablet.
< application of Enalapril maleate and Furosemide compound tablets >
The enalapril maleate and furosemide maleate compound tablet can be applied to the preparation of the pet heart failure treatment.
The technical content of the present invention will be further described with reference to examples. The following examples are illustrative and not intended to be limiting, and are not intended to limit the scope of the invention. The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The present invention will be further described with reference to the following examples.
Example 1:
the enalapril maleate and furosemide compound tablet of this example includes 2.5g of enalapril maleate and 25g of furosemide.
The compound tablet formulation of this example is shown in table 1.
Table 1 example 1 prescription watch (1000 pieces)
*: is a solvent for the binder and is removed during the manufacturing process.
The preparation method of the enalapril maleate and furosemide compound tablet comprises the following steps:
(1) and preparing a mixed material of the enalapril maleate medicine-containing layer:
(a) PEG 3350 was heated to 60 ℃ and melted completely to a liquid.
(b) Enalapril maleate is crushed and sieved by a 100-mesh sieve, and then added into PEG 3350 liquid to be stirred into uniform suspension.
(c) The enalapril maleate PEG 3350 suspension is sprayed and cooled for granulation by a hot melt spraying and cooling granulation device.
(d) The collected granules are sieved, 100-mesh granules are collected, and then the granules are mixed with direct-compression lactose
Mixing with glyceryl behenate to obtain the mixture of enalapril maleate containing medicine layer.
(2) And preparing a mixed material of the blank isolation layer:
(a) direct compression lactose
Adding microcrystalline cellulose 102, CMS-Na and glyceryl behenate into a mixer, and mixing uniformly to obtain a mixture of the blank isolation layer.
(3) And preparing a mixed material of the furosemide medicine-containing layer:
(a) the furosemide, the lactose powder, the microcrystalline cellulose 101 and the CMS-Na are respectively sieved by a 100-mesh sieve and added into a wet granulator.
(b) PVP-K30 was added to purified water to make a solution, which served as a binder.
(c) The granulation was performed using aqueous PVP-K30 solution.
(d) And (3) drying the wet furosemide granules, and finishing the granules and sieving the granules by a 20-mesh sieve to obtain the furosemide granules.
(e) Then mixing the furosemide granules with silicon dioxide, hydrogenated castor oil and glyceryl behenate uniformly to obtain a mixed material of the furosemide medicine-containing layer.
(4) And tabletting:
(a) and (3) selecting a multi-layer tablet rotary tablet press, sequentially adding the mixed materials of the enalapril maleate medicine-containing layers into a first hopper clockwise, and adjusting filling until the required weight is obtained.
(b) The mixture of the blank barrier layer was then added to a second hopper and the filling adjusted until the desired weight was obtained.
(c) And finally, adding the mixed material of the furosemide medicine-containing layer into a third hopper, and adjusting the filling until the required weight is obtained.
(d) Finally, the three layers of materials are compressed to form a multi-layer tablet, namely the enalapril maleate and furosemide compound tablet.
Example 2:
the enalapril maleate and furosemide compound tablet of this example includes 5g of enalapril maleate and 50g of furosemide.
The compound tablet formulation of this example is shown in table 2.
Table 2 example 2 prescription watch (1000 pieces)
*: is a solvent for the binder and is removed during the manufacturing process.
The preparation method of this example is the same as example 1, but is omitted.
Example 3:
the enalapril maleate and furosemide compound tablet of this example includes 10g of enalapril maleate and 100g of furosemide.
The compound tablet formulation of this example is shown in table 3.
Table 3 example 3 prescription watch (1000 pieces)
*: is a solvent for the binder and is removed during the manufacturing process.
The preparation method of this example is the same as example 1, but is omitted.
Comparative example 1:
a batch of enalapril maleate and furosemide compound tablets are produced by adopting a preparation method of common tablets.
The enalapril maleate and furosemide compound tablet of the present comparative example included 2.5g of enalapril maleate and 25g of furosemide.
TABLE 4 COMPARATIVE EXAMPLE 1 prescription Table (1000 tablets)
*: is a solvent for the binder and is removed during the manufacturing process.
Comparative example 2:
enalapril maleate tablets from manufacturer A, purchased from the market, having the following specifications: 2.5 g.
To examine the quality of the product, the above examples were subjected to stability tests and compared with comparative examples.
(I) accelerated test
According to the stability test method of the China veterinary pharmacopoeia 2020 edition, the conditions of the accelerated test are that the temperature is 40 +/-2 ℃ and the relative humidity is 75 +/-5%. After the samples of example 1, example 2 and example 3 were packaged by double aluminum blister, they were placed in an environment of accelerated test, and samples were taken at 0 month, 1 month, 2 months, 3 months and 6 months, respectively, to measure the content of enalapril maleate and furosemide maleate and the related substances, and the test results are shown in table 5:
TABLE 5 accelerated test Enalapril maleate and Furosemide contents and related materials data
As can be seen from Table 5 and FIGS. 1 to 4, the contents of enalapril maleate and furosemide maleate and corresponding impurities of the samples of example 1, example 2 and example 3 of the present invention all meet pharmacopeia standards and have good stability under the conditions of 40 +/-2 ℃ and 75 +/-5% relative humidity. Comparative example 1 the impurities had increased significantly already at 3 months, exceeding pharmacopoeia standards. The comparative example 2 meets the pharmacopoeia standard, but the content is reduced more, and the impurities are obviously increased and are close to the limit standard. The examples are significantly better than the comparative examples.
(II) Long term test
According to the stability test method of the 2020 edition of Chinese animal pharmacopoeia, the long-term test conditions are that the temperature is 25 +/-2 ℃ and the relative humidity is 60 +/-5%. After the samples of example 1, example 2 and example 3 were packaged by double aluminum blister, they were placed in a long-term test environment, and were sampled at 0 month, 3 months, 6 months, 12 months, 18 months and 24 months, respectively, to test the content of enalapril maleate and furosemide maleate and related substances, and the test results are shown in table 6:
TABLE 6 Long-term test Enalapril maleate and Furosemide contents and related material data
As can be seen from Table 6 and FIGS. 5 to 8, the contents of enalapril maleate and furosemide maleate and corresponding impurities of the samples of example 1, example 2 and example 3 of the present invention all meet pharmacopeia standards and have good stability under the conditions of a temperature of 25 +/-2 ℃ and a relative humidity of 60 +/-5%. Comparative example 1 the impurities had increased significantly at 6 months, exceeding the pharmacopoeia standards at 12 months. The comparative example 2 meets the pharmacopoeia standard, but the content is reduced more, and the impurities are obviously increased and are close to the limit standard. The examples are significantly better than the comparative examples.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments and the generic principles defined herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments. Those skilled in the art should appreciate that many modifications and variations are possible in light of the above teaching without departing from the scope of the invention.
Claims (10)
1. An enalapril maleate and furosemide compound tablet is characterized in that: the enalapril maleate medicinal layer comprises an enalapril maleate medicinal layer, a blank isolating layer and a furosemide medicinal layer, wherein the blank isolating layer is positioned between the enalapril maleate medicinal layer and the furosemide medicinal layer;
the mixed material of the enalapril maleate medicine-containing layer comprises enalapril maleate coated particles/powder;
the mixed material of the blank isolation layer comprises a filling agent, a disintegrating agent and a lubricating agent;
the mixed material of the furosemide medicine-containing layer comprises furosemide and auxiliary materials.
2. The enalapril maleate and furosemide compound tablet according to claim 1, wherein: the enalapril maleate coated particles/powder comprise enalapril maleate and low-melting-point auxiliary materials in a mass ratio of 1:10-1: 20.
3. The enalapril maleate and furosemide maleate compound tablet according to claim 2, wherein: the low-melting point auxiliary material is selected from more than one of glyceryl behenate, glyceryl monostearate, glyceryl distearate, polyoxyethylene hydrogenated castor oil, glyceryl monolinoleate or solid polyethylene glycol.
4. The enalapril maleate and furosemide compound tablet according to claim 1, wherein: the enalapril maleate coated particle/powder also comprises other auxiliary materials, and the other auxiliary materials comprise a filling agent and a lubricating agent.
5. The enalapril maleate and furosemide compound tablet according to claim 4, wherein: the filler is direct-pressure lactose; and/or the presence of a gas in the gas,
the lubricant is more than one selected from glyceryl behenate and hydrogenated castor oil.
6. The enalapril maleate and furosemide compound tablet according to claim 1, wherein: the filling agent in the mixture of the blank isolation layer is selected from more than one of direct-pressure lactose, microcrystalline cellulose and pregelatinized starch; and/or the presence of a gas in the gas,
the disintegrant in the mixture of the blank isolating layer is selected from more than one of croscarmellose sodium, crospovidone and carboxymethyl starch sodium; and/or the presence of a gas in the gas,
the lubricant in the mixed material of the blank isolation layer is selected from more than one of glyceryl behenate, hydrogenated castor oil and stearic acid.
7. The enalapril maleate and furosemide compound tablet according to claim 1, wherein: the auxiliary materials in the mixed material of the furosemide medicine-containing layer comprise a filling agent, a disintegrating agent, an adhesive, a flow aid and a lubricating agent.
8. The enalapril maleate and furosemide compound tablet according to claim 7, wherein: the filler is selected from more than one of microcrystalline cellulose, lactose and pregelatinized starch; and/or the presence of a gas in the gas,
the disintegrant is selected from more than one of croscarmellose sodium, crospovidone, carboxymethyl starch sodium and pregelatinized starch; and/or the presence of a gas in the gas,
the adhesive is selected from more than one of povidone and hydroxypropyl methyl cellulose; and/or the presence of a gas in the gas,
the glidant is silicon dioxide; and/or the presence of a gas in the gas,
the lubricant is more than one selected from glyceryl behenate and hydrogenated castor oil.
9. A process for preparing enalapril maleate and furosemide compound tablets according to any one of claims 1 to 8, wherein the process comprises the following steps: which comprises the following steps:
(1) and preparing a mixed material of the enalapril maleate medicine-containing layer: after the low-melting auxiliary materials are melted, adding enalapril maleate powder, stirring and mixing to obtain enalapril maleate coated particles/powder; mixing the enalapril maleate coated particles/powder with other auxiliary materials to obtain a mixed material of the enalapril maleate drug-containing layer;
(2) and preparing a mixed material of the blank isolation layer: mixing the filler, the disintegrant and the lubricant to obtain a mixed material of the blank isolation layer;
(3) and preparing a mixed material of the furosemide medicine-containing layer: mixing furosemide, a filling agent and a disintegrating agent, performing wet granulation by using an adhesive, adding a flow aid and a lubricant, and uniformly mixing to obtain a mixed material of the furosemide medicine-containing layer;
(4) sequentially adding the mixture of the enalapril maleate medicine-containing layer, the mixture of the blank isolating layer and the mixture of the furosemide medicine-containing layer into a hopper for mixing, and tabletting to obtain the enalapril maleate and furosemide compound tablet.
10. Use of enalapril maleate and furosemide compound tablets according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of heart failure in pets.
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| CN115737586A (en) * | 2022-12-06 | 2023-03-07 | 南京比逊医药科技有限公司 | Preparation method of calcium carbonate D3 tablet with stable components |
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| CN2798942Y (en) * | 2005-06-14 | 2006-07-26 | 合肥天元医药研究所 | Aspirin dipyridamole slow-release tablet |
| CN103494818A (en) * | 2013-10-14 | 2014-01-08 | 南京正大天晴制药有限公司 | Nicotinic acid and simvastatin sustained release tablets and method for manufacturing same |
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