Isosorbide mononitrate osmotic pump controlled-release tablet and preparation method thereof

Abstract

The invention discloses an isosorbide mononitrate osmotic pump controlled-release tablet and a preparation method thereof, and relates to the technical field of pharmaceutical preparations. An isosorbide mononitrate osmotic pump controlled-release tablet of the invention comprises a booster layer, wherein drug-containing layers are arranged above and below the booster layer, and the booster layer and the drug-containing layer are wrapped with a semipermeable membrane coating layer, and the semipermeable membrane coating layer is provided with drug-releasing holes. The isosorbide mononitrate osmotic pump controlled-release tablet of the invention has a three-layer tablet core structure of "drug-containing layer-boosting layer-drug-containing layer", and drug-releasing holes are provided in the semipermeable membrane coating layer to achieve a sustained-release effect, so that the dissolution amount increases slowly, the sustained-release effect is good, the release is stable, the effect is long-lasting, and multiple administrations can be avoided.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, in particular to an isosorbide mononitrate osmotic pump controlled-release tablet and a preparation method thereof. Background Art

[0002] Isosorbide mononitrate is the main biologically active metabolite of isosorbide dinitrate. It is a nitrate drug for the long-term treatment of coronary heart disease and angina pectoris. It has been listed in more than ten countries in Europe and the United States and is widely used in clinical practice. my country imported the drug in 1988 and it was widely welcomed by patients. Its main mechanism of action is to dilate venous capacitance vessels and peripheral resistance vessels, reduce the preload and postload of the heart, and reduce myocardial oxygen consumption. The drug not only has the characteristics of rapid and complete absorption, no first-pass effect, high bioavailability, long duration of action, and high clinical efficacy, but also has outstanding advantages such as small individual differences and low toxicity. It can prevent and reduce the development of drug resistance in patients and is a new generation of vasodilator drugs for the prevention and treatment of angina pectoris and myocardial infarction.

[0003] At present, the common tablets and capsules commonly used in clinical practice in China have the disadvantages of short duration, multiple doses per day, and easy side effects; while sustained-release preparations can alleviate these problems to a certain extent, they still have disadvantages such as large individual differences and unstable drug release rate. Osmotic pump controlled-release preparations are a new type of controlled-release preparation that can effectively solve the above problems and have the advantages of convenient administration, long-lasting effect, stable release, and few side effects. Summary of the invention

[0004] In view of the above-mentioned technical deficiencies, the purpose of the present invention is to provide an isosorbide mononitrate osmotic pump controlled-release tablet and a preparation method thereof, which can control the release rate of the isosorbide mononitrate osmotic pump controlled-release tablet and has the advantages of convenient administration, long-lasting effect, stable release and few side effects.

[0005] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0006] The present invention provides an isosorbide mononitrate osmotic pump controlled-release tablet, characterized in that it comprises a boosting layer, the boosting layer is provided with drug-containing layers above and below, the boosting layer and the drug-containing layer are wrapped with a semipermeable membrane coating layer, and the semipermeable membrane coating layer is provided with drug-releasing holes;

[0007] The drug-containing layer comprises:

[0008]

[0009] The boosting layer comprises:

[0010]

[0011] The semipermeable membrane coating layer comprises:

[0012]

[0013] Preferably, the osmotically active substance is selected from one or more of sodium chloride, potassium chloride, mannitol, lactose, and sucrose;

[0014] The filler includes one or more of hydroxypropyl methylcellulose, sodium carboxymethyl starch, mannitol, lactose, sucrose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose;

[0015] The binder includes one or more of hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, and hypromellose;

[0016] The lubricant includes one or more of magnesium stearate, zinc stearate, talcum powder, sodium stearyl fumarate, and micro-powder silica gel;

[0017] The penetration enhancer includes one or more of polyoxyethylene and ethyl cellulose;

[0018] The controlled release coating material includes cellulose acetate, ethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, etc.;

[0019] The plasticizer includes one or more of polyethylene glycol 1000, polyethylene glycol 4000, gum arabic, triethyl citrate, poloxamer, and vitamin E polyethylene glycol succinate;

[0020] The porogen includes at least one of polyethylene glycol or mannitol;

[0021] The pigment includes at least one of red iron oxide, yellow iron oxide or purple iron oxide.

[0022] Preferably, the semipermeable membrane coating layer further comprises a solvent, and the solvent is at least one of 50% ethanol, 75% ethanol or a dichloromethane-ethanol (50:50) solution.

[0023] The present invention also provides a method for preparing an isosorbide mononitrate osmotic pump controlled-release tablet, comprising the following steps:

[0024] (1) The raw materials of the drug-containing layer and the booster layer are sieved and mixed respectively, and then granulated, and pressed into a three-layer tablet core of "drug-containing layer-boosting layer-drug-containing layer" by three-time tablet pressing technology;

[0025] (2) Preparation of coating solution: dissolve the controlled release coating material in a solvent, add plasticizer, micro powder silica gel, and yellow iron oxide, stir evenly, and continue stirring with a magnetic stirrer for later use;

[0026] (3) coating the prepared three-layer tablet core with the above coating solution using a coating pan;

[0027] (4) After using laser or machinery to make drug-releasing holes on the surface of the coating film on both sides of the tablet core, isosorbide mononitrate osmotic pump controlled-release tablets are obtained.

[0028] Preferably, the diameter of the drug release hole is 0.3 to 0.35 mm.

[0029] The technical solution of the present invention has the following advantages:

[0030] 1. The isosorbide mononitrate osmotic pump controlled-release tablets of the present invention have a three-layer tablet core structure of "drug-containing layer-boosting layer-drug-containing layer", and at the same time, small drug-releasing holes are opened in the semipermeable membrane coating layer to achieve a sustained-release effect, so that the dissolution amount increases slowly, the sustained-release effect is good, the release is stable, the effect is long-lasting, and multiple dosing can be avoided.

[0031] 2. The preparation method of the isosorbide mononitrate osmotic pump controlled-release tablets of the present invention is simple and can be completed at room temperature, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0033] Figure 1 It is a schematic diagram of the structure of the isosorbide mononitrate osmotic pump controlled-release tablet of the present invention;

[0034] Figure 2 The figure is the release curve of the isosorbide mononitrate osmotic pump controlled-release tablet of the present invention. DETAILED DESCRIPTION

[0035] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0036] The following examples are helpful for understanding the present invention, but the protection scope of the present invention is not limited thereto.

[0037] Embodiment 1:

[0038] Prescription (Specification: 30mg):

[0039]

[0040]

[0041] Preparation method:

[0042] (1) According to the above prescription, the raw materials and excipients of the drug-containing layer tablet core and the booster layer tablet core are sieved and mixed, and then granulated, and pressed into a three-layer tablet core of "drug-containing layer-boosting layer-drug-containing layer" by three-time tablet pressing technology;

[0043] (2) Preparation of coating solution: dissolve cellulose acetate in 75% ethanol, add triethyl citrate, polyethylene glycol 4000, micro powder silica gel, and yellow ferric oxide, stir evenly, and continue stirring with a magnetic stirrer for later use;

[0044] (3) coating the prepared three-layer tablet core with the above coating solution using a coating pan;

[0045] (4) Use a laser or machine to make a small hole with a diameter of about 0.3 mm on the surface of the coating film on both sides of the tablet core. A total of 10,000 tablets are produced. The structure is as follows: Figure 1 shown.

[0046] Embodiment 2:

[0047] Prescription (Specification: 30mg):

[0048]

[0049]

[0050] Preparation method:

[0051] (1) According to the above prescription, the raw materials and excipients of the drug-containing layer tablet core and the booster layer tablet core are sieved and mixed, and then granulated, and pressed into a three-layer tablet core of "drug-containing layer-boosting layer-drug-containing layer" by three-time tablet pressing technology;

[0052] (2) Preparation of coating solution: dissolve cellulose acetate in 75% ethanol, add triethyl citrate, polyethylene glycol 4000, micro powder silica gel, and yellow ferric oxide, stir evenly, and continue stirring with a magnetic stirrer for later use;

[0053] (3) coating the prepared three-layer tablet core with the above coating solution using a coating pan;

[0054] (4) Use a laser or machine to make a small hole with a diameter of about 0.3 mm on the surface of the coating film on both sides of the tablet core. A total of 10,000 tablets are produced.

[0055] Embodiment 3:

[0056] Prescription (Specification: 30mg):

[0057]

[0058]

[0059] Preparation method:

[0060] (1) According to the above prescription, the raw materials and auxiliary materials of the drug-containing layer core and the booster layer core are sieved and mixed, and then granulated, and pressed into a three-layer tablet core of "drug-containing layer-boosting layer-drug-containing layer" by three-time tablet pressing technology, and the tablet core hardness is controlled to be 8-14kp;

[0061] (2) Preparation of coating solution: dissolve cellulose acetate and cellulose acetate phthalate in 50% solvent, add triethyl citrate, mannitol, talcum powder, and yellow iron oxide, stir evenly, and continue stirring with a magnetic stirrer for later use;

[0062] (3) coating the prepared three-layer tablet core with the above coating solution using a coating pan, with a coating weight gain of 5%;

[0063] (4) Use a laser or machine to make a small hole with a diameter of about 0.35 mm on the surface of the coating film on both sides of the tablet core. A total of 10,000 tablets are produced.

[0064] Embodiment 4:

[0065] Prescription (Specification: 30mg):

[0066]

[0067]

[0068] Preparation method:

[0069] (1) According to the above prescription, the raw materials and excipients of the drug-containing layer tablet core and the booster layer tablet core are sieved and mixed, and then granulated, and pressed into a three-layer tablet core of "drug-containing layer-boosting layer-drug-containing layer" by three-time tablet pressing technology;

[0070] (2) Preparation of coating solution: dissolve cellulose acetate in 75% ethanol, add triethyl citrate, mannitol, micro-powdered silica gel, and yellow ferric oxide, stir evenly, and continue stirring with a magnetic stirrer for later use;

[0071] (3) coating the prepared three-layer tablet core with the above coating solution using a coating pan;

[0072] (4) Use laser or machine to punch a small hole with a diameter of about 0.3 mm on the surface of the coating film on both sides of the tablet core, and produce a total of 10,000 tablets.

[0073] Release determination:

[0074] According to the dissolution and release determination method (Chinese Pharmacopoeia 2015 General Rules 0931 First Method), use 500 ml of water as the dissolution medium, the rotation speed is 50 r / min, operate according to this method, take samples at 1, 2, 4, 8, 12, 16, 20, and 24 hours, take 5 ml of the solution respectively, filter, and immediately replenish the dissolution medium of the same temperature and volume, use octadecylsilane bonded silica gel as the filler; use methanol-water (25:75) as the mobile phase; the detection wavelength is 210 nm. Take an appropriate amount of isosorbide mononitrate reference substance and 2-isosorbide mononitrate reference substance, add mobile phase to dissolve and dilute to make a solution containing about 5 mg of each in each 1 ml. The number of theoretical plates calculated based on the isosorbide mononitrate peak is not less than 3000, and the separation degree between the isosorbide mononitrate peak and the 2-isosorbide mononitrate peak should be greater than 2.0. Accurately measure 20 μl of the filtrate, inject it into the high performance liquid chromatograph, and record the chromatogram; calculate the dissolution amount of each tablet at different times by peak area according to the external standard method. The experimental results are shown in Table 1 and Figure 2 .

[0075] Table 1 Dissolution amount of different embodiments

[0076] Time / h Example 1 Example 2 Example 3 Example 4 1 7.02％ 6.89％ 8.32％ 7.15％ 2 15.23％ 16.01％ 18.55％ 15.75％ 4 27.15％ 29.32％ 29.03％ 28.77％ 8 52.64％ 50.96％ 54.06％ 49.96％ 12 75.57％ 75.15％ 77.22％ 72.05％ 16 96.82％ 97.28％ 94.37％ 96.32％ 20 98.87％ 100.08％ 98.32％ 99.35％ 24 99.32％ 100.02％ 98.78％ 99.72％

[0077] From Table 1 and Figure 2 It can be seen that the dissolution amount of the drug of the present invention increases slowly, the sustained-release effect is good, the release is stable, the effect is long-lasting, and multiple administrations can be avoided.

Claims

1. An isosorbide mononitrate osmotic pump controlled-release tablet, characterized in that: It comprises a boosting layer, wherein the boosting layer is provided with drug-containing layers above and below, the boosting layer and the drug-containing layer are wrapped with a semipermeable membrane coating layer, and the semipermeable membrane coating layer is provided with drug-releasing holes; The drug-containing layer comprises: The boosting layer comprises: The semipermeable membrane coating layer comprises:

2. The isosorbide mononitrate osmotic pump controlled-release tablet according to claim 1, characterized in that: The osmotically active substance is selected from one or more of sodium chloride, potassium chloride, mannitol, lactose, and sucrose; The filler includes one or more of hydroxypropyl methylcellulose, sodium carboxymethyl starch, mannitol, lactose, sucrose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; The binder includes one or more of hydroxypropyl cellulose, povidone, sodium carboxymethyl cellulose, and hypromellose; The lubricant includes one or more of magnesium stearate, zinc stearate, talcum powder, sodium stearyl fumarate, and micro-powder silica gel; The penetration enhancer includes one or more of polyoxyethylene and ethyl cellulose; The controlled release coating material includes cellulose acetate, ethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, etc.; The plasticizer includes one or more of polyethylene glycol 1000, polyethylene glycol 4000, gum arabic, triethyl citrate, poloxamer, and vitamin E polyethylene glycol succinate; The porogen includes at least one of polyethylene glycol or mannitol; The pigment includes at least one of red iron oxide, yellow iron oxide or purple iron oxide.

3. The isosorbide mononitrate osmotic pump controlled-release tablet according to claim 1, characterized in that: The semipermeable membrane coating layer further comprises a solvent, and the solvent is at least one of 50% ethanol, 75% ethanol or a dichloromethane-ethanol (50:50) solution.

4. The method for preparing an isosorbide mononitrate osmotic pump controlled-release tablet according to any one of claims 1 to 3, characterized in that: The steps include: (1) The raw materials of the drug-containing layer and the booster layer are sieved and mixed respectively, and then granulated, and pressed into a three-layer tablet core of "drug-containing layer-boosting layer-drug-containing layer" by three-time tablet pressing technology; (2) Preparation of coating solution: dissolve the controlled release coating material in a solvent, add plasticizer, micro powder silica gel, and yellow iron oxide, stir evenly, and continue stirring with a magnetic stirrer for later use; (3) coating the prepared three-layer tablet core with the above coating solution using a coating pan; (4) After using laser or machinery to make drug-releasing holes on the surface of the coating film on both sides of the tablet core, isosorbide mononitrate osmotic pump controlled-release tablets are obtained.

5. The method for preparing an isosorbide mononitrate osmotic pump controlled-release tablet according to claim 4, characterized in that: The diameter of the drug-releasing hole is 0.3 to 0.35 mm.

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