CN111603450B - Isosorbide mononitrate tablet and preparation process thereof - Google Patents
Isosorbide mononitrate tablet and preparation process thereof Download PDFInfo
- Publication number
- CN111603450B CN111603450B CN201910133734.XA CN201910133734A CN111603450B CN 111603450 B CN111603450 B CN 111603450B CN 201910133734 A CN201910133734 A CN 201910133734A CN 111603450 B CN111603450 B CN 111603450B
- Authority
- CN
- China
- Prior art keywords
- isosorbide mononitrate
- tablet
- proline
- isosorbide
- sheet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an isosorbide mononitrate tablet and a preparation process thereof. The isosorbide mononitrate tablet provided by the invention comprises active ingredients of isosorbide mononitrate, L-proline, kaolin and other pharmaceutically acceptable auxiliary materials, wherein the weight ratio of isosorbide mononitrate to L-proline to kaolin is 1:0.1-0.4:0.5-1.5, and the other pharmaceutically acceptable auxiliary materials comprise a filler, an adhesive, a disintegrating agent and a lubricant. The isosorbide mononitrate tablet prepared by the invention has good stability, is not easy to crystallize in the storage process, is quickly dissolved out and is beneficial to improving the bioavailability.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an isosorbide mononitrate tablet and a preparation process thereof.
Background
Isosorbide Mononitrate (Isosorbide Mononitrate) is known as 1, 4, 3, 6-dianhydro-D-sorbitol-5-nitrate, has a molecular formula of C6H9NO6 and a molecular weight of 191.14, is a white needle-shaped crystal or crystalline powder, is easily soluble in methanol or acetone, is soluble in chloroform or water, is almost insoluble in hexane, has a solubility of more than 250mg/mL in each medium of ph1.0 to ph6.8, belongs to a high-solubility drug, and has a structural formula as follows:
isosorbide mononitrate is the main bioactive metabolite of isosorbide mononitrate, is a new generation of nitrate antianginal drug, is suitable for long-term treatment of coronary heart disease, prevention of angina pectoris and treatment of persistent angina after myocardial infarction, and can be used in combination with digitalis and/or diuretics to treat chronic congestive heart failure. Clinical research results show that the medicine has the characteristics of rapid absorption, no first-pass effect, high bioavailability, wide effective concentration range, long duration of action of the medicine, high clinical curative effect and the like, has the outstanding advantages of small individual difference, low toxicity and the like, and is one of the best medicines for preventing and treating angina at present. At present, isosorbide mononitrate dosage forms on the market comprise tablets, dispersible tablets, sustained-release capsules, sustained-release tablets and the like.
Isosorbide mononitrate has a low melting point, and raw materials are easy to separate out and crystallize in the preparation and storage processes. In order to solve the problem, in patent CN103610650B, lactose is used as a stabilizer, povidone represented by PVP K90, copovidone, and the like are used as a binder and a crystal inhibitor, so that the remarkable change of the in vitro release degree of the drug caused by crystallization of isosorbide mononitrate is avoided. PVP K90 has higher viscosity, the effect of inhibiting crystallization is poorer when the dosage is less, the dissolution is slower when the dosage is larger, and PVP K90 adopted in the sustained-release preparation is not thickly enough, but if the sustained-release preparation is applied to a common tablet, the dissolution is slower inevitably, so that the sustained-release preparation has problems in the aspects of in-vitro similarity and in-vivo bioequivalence with the original preparation.
Patent application CN104055744A provides an isosorbide mononitrate tablet and a preparation method thereof, the tablet contains crospovidone and other pharmaceutically usable auxiliary materials, and good stability can be realized without adding a large amount of adhesive to inhibit crystal precipitation. According to the invention, the weight ratio of isosorbide mononitrate to crospovidone is 1:1-3, the minimum specification of the existing isosorbide mononitrate tablet is 20mg, and the dosage of each crospovidone is calculated to be 20-60mg, so that the cross-linked povidone is extremely easy to absorb moisture, and pocks are easy to appear on the surface of the tablet when too much dosage is used.
The prior art does not mention the technical scheme which can avoid the crystallization of the medicine, has better tablet surface, lower impurity content and higher dissolution rate.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide an isosorbide mononitrate tablet and a preparation process thereof. The isosorbide mononitrate tablet provided by the invention is not easy to crystallize, and has high stability and rapid drug dissolution.
Aiming at the problem that isosorbide mononitrate tablets are prone to crystallization, the inventor firstly adds high-molecular polymers or porous substances such as crospovidone, silicon dioxide and the like, and through a large number of experiments, the crystallization inhibiting effect is not obvious. In the process of screening the auxiliary materials, the inventor unexpectedly finds that the kaolin has a certain crystal inhibition effect, but the acceleration stability is still poor. Then, the inventor tries to add amino acid substances and kaolin to achieve the purpose of stabilizing the isosorbide mononitrate, so that the preparation added with the L-proline is not easy to crystallize, but does not have the effect when other amino acids are used, and the structure of the preparation is related to the existence of the pyrrolidinyl.
Specifically, the purpose of the invention is realized by the following technical scheme:
an isosorbide mononitrate tablet comprises active ingredients of isosorbide mononitrate, L-proline, kaolin and other pharmaceutically acceptable auxiliary materials.
The weight ratio of the isosorbide mononitrate to the L-proline to the kaolin is 1 (0.1-0.3) to 0.5-1.5.
Preferably, the weight ratio of isosorbide mononitrate to L-proline to kaolin is 1:0.2: 1.
The pharmaceutically acceptable other auxiliary materials comprise a filler, a binder, a disintegrant and a lubricant.
Preferably, the filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, lactose and starch.
Preferably, the binder is selected from one or more of hydroxypropyl cellulose, hypromellose and povidone.
Preferably, the disintegrating agent is selected from one or more of sodium carboxymethyl starch, crospovidone, sodium croscarmellose and low-substituted hydroxypropyl cellulose.
Preferably, the lubricant is selected from one or more of magnesium stearate, magnesium aluminum silicate and sodium stearate fumarate.
The isosorbide mononitrate tablet comprises the following components in parts by weight:
meanwhile, the invention provides a preparation process of the isosorbide mononitrate tablet, which comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution for later use;
(2) weighing a filler, an adhesive and a disintegrating agent, adding into a fluidized bed, uniformly mixing, spraying the mixed solution obtained in the step (1), granulating, drying and finishing to obtain isosorbide mononitrate granules for later use;
(3) and (3) uniformly mixing the isosorbide mononitrate particles obtained in the step (2) with a lubricant, and tabletting to obtain the isosorbide mononitrate tablet.
Compared with the prior art, the isosorbide mononitrate tablet is not easy to crystallize in the storage process, has high stability and quick drug dissolution, and is beneficial to improving the bioavailability. In addition, isosorbide mononitrate belongs to nitrate drugs, and is easy to explode in the crushing and sieving processes.
Detailed Description
The invention will be further described by the following description of specific embodiments, it being properly understood that: the examples of the present invention are provided for illustration only and not for limitation of the present invention. Therefore, simple modifications of the present invention in the process of the present invention are within the scope of the claimed invention.
All raw materials and reagents in the invention are commercially available.
EXAMPLE 1 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing microcrystalline cellulose, hydroxypropyl cellulose and sodium carboxymethyl starch according to the prescription amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate granules prepared in the step (2) with magnesium stearate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
EXAMPLE 2 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose according to the formula, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate particles;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
EXAMPLE 3 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing the formula amounts of pregelatinized starch, microcrystalline cellulose, povidone K30 and crospovidone XL-10, adding into a fluidized bed, mixing uniformly, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with aluminum magnesium silicate, punching the tablets with a shallow arc of phi 8mm and the hardness of 50-80N to obtain the isosorbide mononitrate tablets.
Example 4 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, povidone K30 and sodium carboxymethyl starch according to the prescription amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with aluminum magnesium silicate, punching the tablets with a shallow arc of phi 8mm and the hardness of 50-80N to obtain the isosorbide mononitrate tablets.
EXAMPLE 5 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
EXAMPLE 6 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, pregelatinized starch, hydroxypropyl cellulose and sodium carboxymethyl cellulose in the formula amount, adding into a fluidized bed, mixing uniformly, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate granules prepared in the step (2) with magnesium stearate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Example 7 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and crospovidone XL-10 according to the formula, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
EXAMPLE 8 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing microcrystalline cellulose, hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with magnesium aluminum silicate, punching a sheet with a diameter of 8mm in a shallow arc, and obtaining the isosorbide mononitrate sheet with the hardness of 50-80N.
Example 9 isosorbide mononitrate tablets
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing the pregelatinized starch, the hydroxypropyl methylcellulose and the croscarmellose sodium in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate granules prepared in the step (2) with magnesium stearate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Example 10 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing mannitol, hydroxypropyl methylcellulose and croscarmellose sodium in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with talcum powder, punching the tablets with a shallow arc of phi 8mm and hardness of 50-80N to obtain the isosorbide mononitrate tablets.
EXAMPLE 11 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing the dextrin, the lactose, the starch slurry and the crosslinked sodium carboxymethyl cellulose according to the prescription amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying and finishing to obtain isosorbide mononitrate particles;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with zinc stearate, punching the tablets by a shallow arc with the diameter of 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
EXAMPLE 12 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing the pregelatinized starch, the povidone K30 and the crospovidone XL-10 according to the prescription amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying and granulating to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with aluminum magnesium silicate, punching the tablets with a shallow arc of phi 8mm and the hardness of 50-80N to obtain the isosorbide mononitrate tablets.
Example 13 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 1 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate into purified water, stirring until the isosorbide mononitrate is completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 2 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate into purified water, stirring until the isosorbide mononitrate is completely dissolved to obtain an isosorbide mononitrate water solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the aqueous solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 3 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and histidine into purified water, stirring until the isosorbide mononitrate and the histidine are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 4 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-lysine into purified water, stirring until the isosorbide mononitrate and the L-lysine are completely dissolved, then adding kaolin, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose according to the formula, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate particles;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 5 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, and stirring until the isosorbide mononitrate and the L-proline are completely dissolved to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching into a shallow arc tablet with the diameter of 8mm, and obtaining the isosorbide mononitrate tablet with the hardness of 50-80N.
Comparative example 6 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring until the isosorbide mononitrate and the L-proline are completely dissolved, then adding talcum powder, and stirring uniformly to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching the tablets with a shallow arc of phi 8mm, and obtaining the isosorbide mononitrate tablets with the hardness of 50-80N.
Comparative example 7 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
weighing the main drug with the prescription amount, fully mixing the main drug with the auxiliary materials of lactose, sodium chloride, povidone K30 and silicon dioxide by an equivalent gradual addition method, sieving and uniformly mixing, then adding a proper amount of 90% ethanol solution to prepare a proper soft material, granulating by a 20-mesh sieve, drying, adding the magnesium stearate with the prescription amount, granulating, fully and uniformly mixing, and tabletting to obtain the isosorbide mononitrate tablet.
Comparative example 8 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
and (3) screening isosorbide mononitrate and crospovidone by a sieve of 80 meshes, weighing according to the prescription, adding microcrystalline cellulose according to the prescription, mixing uniformly, adding magnesium stearate according to the prescription, mixing uniformly, and tabletting to obtain the isosorbide mononitrate tablet.
Comparative example 9 isosorbide mononitrate tablet
Prescription:
the preparation process comprises the following steps:
(1) adding isosorbide mononitrate and povidone K90 into purified water, and stirring until the isosorbide mononitrate and the povidone K90 are completely dissolved to obtain a mixed solution;
(2) weighing lactose, hydroxypropyl methylcellulose and low-substituted hydroxypropyl cellulose in the formula amount, adding into a fluidized bed, uniformly mixing, spraying the mixed solution prepared in the step (1), granulating, drying, and grading to obtain isosorbide mononitrate granules;
(3) and (3) uniformly mixing the isosorbide mononitrate particles prepared in the step (2) with sodium stearate fumarate, punching into a shallow arc tablet with the diameter of 8mm, and obtaining the isosorbide mononitrate tablet with the hardness of 50-80N.
Verification examples
1. Test materials: isosorbide mononitrate tablets and original formulations prepared in examples 1-13 and comparative examples 1-9.
2. Test method
(1) Stability test
Placing the sample in a room temperature environment, and inspecting the appearance of each isosorbide mononitrate tablet sample at month 6; referring to the requirements of 'Chinese pharmacopoeia' (2015 edition) appendix <9001 raw material medicament and preparation stability test guiding principle >, a sample is placed in a constant temperature incubator with the temperature of 40 +/-2 ℃ and the relative humidity of 75 +/-10%, appearance characters of each isosorbide mononitrate tablet sample at 0 th month and 6 th month of various products are inspected, and the content (%) of related substances is tested.
The related substance content test method comprises the following steps: grinding the sample to prepare solution containing lmg in lmL as test solution; and taking a proper amount of an isosorbide dinitrate reference substance and an isosorbide 2-mononitrate reference substance, precisely weighing, adding a mobile phase for dissolving and quantitatively diluting to prepare a mixed solution containing about 0.25mg of each lmL, precisely weighing 2mL, placing in a 200mL measuring flask, precisely adding a test solution lmL, diluting to a scale with the mobile phase, and shaking uniformly to obtain the reference solution. And (3) injecting 20 mu L of the control solution into a liquid chromatograph, adjusting the detection sensitivity to enable the peak height of the isosorbide mononitrate peak to be about 25% of the full range, precisely measuring 20 mu L of each of the test solution and the control solution, injecting the test solution and the control solution into the liquid chromatograph, and recording the chromatogram until the retention time of the isosorbide mononitrate peak is 1.1 times. If chromatographic peaks consistent with retention time of isosorbide dinitrate and isosorbide 2-mononitrate exist in a chromatogram of the test solution, the chromatographic peaks are not more than 0.25 percent calculated by the peak area according to an external standard method; the peak area of other single impurities is not more than 0.5 times (0.25%) of the peak area of isosorbide mononitrate in the control solution, and the total amount of the impurities is not more than 0.5%.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; methanol-water (25: 75) as mobile phase; the detection wavelength is 210 nm. Taking a proper amount of isosorbide mononitrate and 2-isosorbide mononitrate as reference substances, adding mobile phase for dissolving and diluting to prepare solutions containing about 5 mu g of each lmL, taking 20 mu L of human-injection liquid chromatograph, wherein the theoretical plate number is not less than 3000 according to the peak of isosorbide mononitrate, and the separation degree of the peak of isosorbide mononitrate and the peak of 2-isosorbide mononitrate is more than 2.0.
(2) Dissolution test
The samples were placed in a constant temperature incubator at 40. + -. 2 ℃ and a relative humidity of 75. + -. 10% to test the dissolution rate at month 0 and month 6. A sample was taken, and the solution was filtered at 5 and 10 minutes according to the dissolution method (0931, the general rule of the four departments of the 2015 edition, China pharmacopoeia) using 900mL of water as dissolution medium and 50 rpm, and 20. mu.L of filtrate was accurately obtained and injected into a liquid chromatograph, and the chromatogram was recorded. And precisely weighing isosorbide mononitrate as a reference substance, adding a dissolving-out medium to dissolve the isosorbide mononitrate, quantitatively diluting the isosorbide mononitrate with the dissolved medium to prepare solution containing about 22 mu g of the isosorbide mononitrate in lmL, and measuring by the same method. The elution amount of each tablet was calculated by peak area according to the external standard method.
Chromatographic conditions and stability test.
3. And (3) test results: the test results are shown in tables 1, 2 and 3.
TABLE 1 isosorbide mononitrate tablets appearance characteristics
| Sample (I) | 0 month | Room temperature for 6 months | Accelerated for 6 months |
| Example 1 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 2 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 3 | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 4 | One side of the sheet is smooth and clean | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 5 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 6 | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean | The surface of the sheet is smooth and clean |
| Example 7 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 8 | The surface of the sheet is smooth and clean | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 9 | One side of the sheet is smooth and clean | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 10 | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 11 | One side of the sheet is smooth and clean | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 12 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Example 13 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
| Comparative example 1 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 2 | The surface of the sheet is smooth and clean | A large amount of crystals are separated out | A large amount of crystals are separated out |
| Comparative example 3 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 4 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 5 | The surface of the sheet is smooth and clean | One side of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 6 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 7 | The surface of the sheet is smooth and clean | The surface of the sheet is smooth and clean | A small amount of crystals are separated out |
| Comparative example 8 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | Pocked on the surface of the sheet |
| Comparative example 9 | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean | One side of the sheet is smooth and clean |
Through tests, the isosorbide mononitrate tablets prepared in the examples 1 to 13 of the invention have high stability, have smooth surfaces and no crystallization phenomenon after 6-month accelerated tests, and the comparative examples 1 to 6 have crystallization at different degrees, which shows that the L-proline and kaolin are used together to have better crystal inhibition effect; comparative examples 7 and 8 respectively use silicon dioxide and crospovidone as crystal inhibitors, and the stability is lower than that of the embodiment of the invention.
Table 2 isosorbide mononitrate tablet related substance content (%)
Through tests, after the isosorbide mononitrate tablets of the embodiments 1 to 13 of the invention are accelerated for 6 months, the increase of related substances is not obvious (see table 2), and the isosorbide mononitrate tablets are superior to the original developers; the contents of related substances in the comparative examples 1 to 6 are increased to a certain extent, which shows that the combination action of the L proline and the kaolin can improve the stability of the isosorbide mononitrate tablet and prevent the substances from going bad; the increase ratio of the total impurity content in comparative examples 7 and 8 was higher than that in the examples of the present invention; the prescription of comparative example 9 contains povidone K90, and the content increase ratio of related substances is large.
TABLE 3 dissolution of isosorbide mononitrate tablets
Through tests, the isosorbide mononitrate tablets prepared in examples 1-13 of the invention still dissolve rapidly after 6 months of accelerated tests (see table 3), the dissolution rate of comparative example 8 in 5min is obviously weaker than that of the invention, and the dissolution rate of comparative example 9 is slower by taking povidone K90 as a crystal inhibitor.
Claims (8)
1. The isosorbide mononitrate tablet is characterized by comprising active ingredients of isosorbide mononitrate, L-proline, kaolin and other pharmaceutically acceptable auxiliary materials, wherein the weight ratio of the isosorbide mononitrate to the L-proline to the kaolin is 1:0.1-0.3: 0.5-1.5.
2. The isosorbide mononitrate tablet of claim 1, wherein the weight ratio of isosorbide mononitrate to L-proline and kaolin is 1:0.2: 1.
3. The isosorbide mononitrate tablet of claim 1, wherein the pharmaceutically acceptable other excipients include a filler, a binder, a disintegrant, and a lubricant.
4. The isosorbide mononitrate tablet of claim 3, wherein the filler is selected from one or more of microcrystalline cellulose, pregelatinized starch, lactose, starch.
5. The isosorbide mononitrate tablet of claim 3, wherein the binder is selected from one or more of hydroxypropyl cellulose, hypromellose, povidone.
6. The isosorbide mononitrate tablet of claim 3, wherein the disintegrant is selected from the group consisting of one or more of sodium starch glycolate, crospovidone, sodium croscarmellose and low substituted hydroxypropylcellulose.
7. The isosorbide mononitrate tablet of claim 3, wherein the lubricant is selected from one or more of magnesium stearate, magnesium aluminum silicate, sodium fumarate stearate.
8. The process for preparing an isosorbide mononitrate tablet of any one of claims 1-7, comprising the steps of:
(1) adding isosorbide mononitrate and L-proline into purified water, stirring and dissolving, then adding kaolin, and uniformly stirring to obtain a mixed solution for later use;
(2) weighing a filler, an adhesive and a disintegrating agent, adding into a fluidized bed, uniformly mixing, spraying the mixed solution obtained in the step (1), granulating, drying and finishing to obtain isosorbide mononitrate granules for later use;
(3) and (3) uniformly mixing the isosorbide mononitrate particles obtained in the step (2) with a lubricant, and tabletting to obtain the isosorbide mononitrate tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910133734.XA CN111603450B (en) | 2019-02-22 | 2019-02-22 | Isosorbide mononitrate tablet and preparation process thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910133734.XA CN111603450B (en) | 2019-02-22 | 2019-02-22 | Isosorbide mononitrate tablet and preparation process thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111603450A CN111603450A (en) | 2020-09-01 |
| CN111603450B true CN111603450B (en) | 2022-09-23 |
Family
ID=72193709
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910133734.XA Active CN111603450B (en) | 2019-02-22 | 2019-02-22 | Isosorbide mononitrate tablet and preparation process thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111603450B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113509446A (en) * | 2021-05-31 | 2021-10-19 | 辰欣药业股份有限公司 | Isosorbide mononitrate tablet and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1679536A (en) * | 2004-04-07 | 2005-10-12 | 鲁南制药集团股份有限公司 | Single nitrate isosorbide delayed-release tablets |
| CN101095661A (en) * | 2007-07-23 | 2008-01-02 | 南昌弘益科技有限公司 | Isosorbide mononitrate orally disintegrating tablets |
| CN104055744A (en) * | 2014-07-18 | 2014-09-24 | 鲁南制药集团股份有限公司 | Isosorbide mononitrate tablet and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU1323400A (en) * | 1998-10-27 | 2000-05-15 | Fuisz Technologies Ltd. | Microparticles containing peg and/or peg glyceryl esters |
-
2019
- 2019-02-22 CN CN201910133734.XA patent/CN111603450B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1679536A (en) * | 2004-04-07 | 2005-10-12 | 鲁南制药集团股份有限公司 | Single nitrate isosorbide delayed-release tablets |
| CN101095661A (en) * | 2007-07-23 | 2008-01-02 | 南昌弘益科技有限公司 | Isosorbide mononitrate orally disintegrating tablets |
| CN104055744A (en) * | 2014-07-18 | 2014-09-24 | 鲁南制药集团股份有限公司 | Isosorbide mononitrate tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111603450A (en) | 2020-09-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3981399A1 (en) | Oral solid tablet comprising bruton's tyrosine kinase inhibitor and preparation method therefor | |
| CN107595784A (en) | Tacrolimus slow releasing medicinal compositions | |
| CN107982223B (en) | Atorvastatin calcium tablet and preparation method thereof | |
| CN109662950B (en) | Pharmaceutical composition containing dapoxetine hydrochloride | |
| JP6215940B2 (en) | 8-[(3R) -3-Amino-1-piperidinyl] -7- (2-butyn-1-yl) -3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) Stable pharmaceutical composition comprising methyl] -1H-purine-2,6-dione or a pharmaceutically acceptable salt thereof | |
| CN103830192A (en) | Tenofovir disoproxil fumarate tablets allowing direct powder compression and preparation method thereof | |
| CN111603450B (en) | Isosorbide mononitrate tablet and preparation process thereof | |
| CN113633616B (en) | A solid preparation with high bioavailability | |
| CN107753455B (en) | A tablet containing imidafenacin and its preparation method | |
| CN103494788B (en) | Pharmaceutical composition of rosuvastatin calcium tablets and preparation method thereof | |
| CN111297823B (en) | Preparation method of oseltamivir phosphate capsule | |
| CN106018618B (en) | Escitalopram oxalate tablet composition and quality control method | |
| CN105828827A (en) | Solid preparation comprising tofogliflozin and method for producing same | |
| CN117547534A (en) | Nicorandil sustained release preparation and preparation method thereof | |
| WO2014075583A1 (en) | Stable oral solid drug composition of abiraterone and preparation method therefor | |
| CN114917233B (en) | Pharmaceutical composition containing nucleoside analogue, and preparation method and application thereof | |
| CN107865826B (en) | Solid dispersion of E-configuration benzamide compound | |
| CN111419820B (en) | Desloratadine citrate disodium capsule and preparation method and application thereof | |
| CN116724039A (en) | Oral preparation containing JAK inhibitor or salt or crystal form thereof, and preparation method and application thereof | |
| CN114272219A (en) | Donepezil hydrochloride tablet and preparation method thereof | |
| CN113827576A (en) | Pharmaceutical composition with active ingredient of naloxone oxalate and preparation method thereof | |
| US20080132533A1 (en) | Solid Dispersion Comprising Tacrolimus and Entericcoated Macromolecule | |
| JPH11335302A (en) | Stable medicinal composition | |
| CN109419780B (en) | Sotalol hydrochloride tablet and preparation method thereof | |
| CN106943369B (en) | Pharmaceutical composition of mosapride citrate and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |