CN116251069A - Zolpidem tartrate gastric-floating release tablet and preparation method thereof - Google Patents

Zolpidem tartrate gastric-floating release tablet and preparation method thereof Download PDF

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CN116251069A
CN116251069A CN202111506669.4A CN202111506669A CN116251069A CN 116251069 A CN116251069 A CN 116251069A CN 202111506669 A CN202111506669 A CN 202111506669A CN 116251069 A CN116251069 A CN 116251069A
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sustained
gastric
zolpidem tartrate
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王刚
李心怡
邓文雷
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Shandong New Time Pharmaceutical Co Ltd
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Abstract

The invention belongs to the field of pharmaceutical preparations, and in particular relates to zolpidem tartrate gastric-floating sustained-release tablets and a preparation method thereof. The zolpidem tartrate gastric-floating type sustained release tablet comprises zolpidem tartrate, a swelling agent, a sustained and controlled release material, a filler, a pore-forming agent and a lubricant, wherein the proper combination of a framework material and the swelling agent is selected, so that the retention time of the zolpidem tartrate gastric-floating type sustained release tablet in the stomach is prolonged, the sustained release and absorption of the medicine are realized, the fluctuation of the blood concentration is reduced, the timely release of an insomnia patient in the body after the administration is ensured, and the in-vivo release is in an effective blood concentration range, so that early awakening is prevented, and the sleeping quality is ensured.

Description

Zolpidem tartrate gastric-floating release tablet and preparation method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to zolpidem tartrate gastric-floating sustained-release tablets and a preparation method thereof.
Background
Insomnia is a common psychological and physiological disease, which seriously affects people's daily life. Symptoms of insomnia generally include difficulty falling asleep, superficial sleep, easy wakefulness, and early wakefulness. Wherein, early wake refers to a phenomenon that wakes up 2 to 3 hours or more earlier than normal and cannot fall asleep again. Because the effective acting time of hypnotic drugs is generally 4-6 hours, the traditional pre-sleep administration is not effective for treating early-wake symptoms, and is a blank in the treatment of sleep disorder. If hypnotic drugs with slow release function are taken to prolong sleeping time, the residual effect of the drugs in the next morning is often caused, and normal work and life are affected. In order to provide an effective treatment scheme for early awakening patients, a gastric floating release preparation of hypnotic drugs is developed, so that the patients can obtain an effective blood concentration before awakening about 2 am, and the sleeping time of the patients is prolonged.
Zolpidem Tartrate (Zolpidem-Tartrate) is a new generation of non-benzodiazepine hypnotic agents, with the chemical name N, N6-trimethyl-2- (4-methylphenyl) -imidazo [1,2-a ] pyridine-3-acetamide, a gammA-Aminobutyric acid a-benzodiazepine receptor agonist, marketed in the united states in 1992 and in china in 1998, the product being sinuosi. Zolpidem tartrate sustained release tablets (Ambian CR) were marketed in the United states in 2005. Can selectively antagonize gammA-Aminobutyric acid A (GABA-A) composite receptor to promote GABA, has stronger sedative hypnotic effect, and is only used for hypnosis in clinic. Compared with benzodiazepine medicines, zolpidem has smaller post-enuresis, less tolerance and dependence are generated after the zolpidem is used for a long time, rebound insomnia is hardly caused, and the zolpidem is the first-choice medicine of benzodiazepine medicines.
CN1334729a discloses a sustained release dosage form of zolpidem or a salt thereof, in which the drug contained in the dosage form can exhibit biphasic release at a predetermined time, wherein the first phase is an immediate release phase and the second phase is a sustained release phase.
The patent CN100415216C, CN101884619A CN102552107, CN102600097A and the like disclose sustained release preparations of zolpidem or salts thereof, wherein most of the sustained release preparations are biphasic release mechanisms.
CN101574328A discloses an zolpidem salt pulse pellet preparation for early awakening patients, which is characterized in that an outer time-lag layer is coated by acrylic resin containing quaternary ammonium salt groups, and a medicine layer and an organic acid layer are arranged between a blank pellet core and the time-lag layer. Pellets prepared using this technique had a time lag of about 4 hours with >90% release within 2 hours of time lag.
Regarding sustained-release pulse pellet formulations, CN102764243a discloses a pulse release pellet comprising, in order from inside to outside, a blank pellet core, a drug layer, an isolation layer, a release-regulating layer, and a protective layer. The release regulating layer consists of enteric materials dissolved at different pH values, polybasic acid/salt, plasticizer and anti-adhesion agent, so that the release of the micropill is related to the pH value, and a gap is generated among different individuals.
CN101269056a and CN101269059a disclose a preparation method of pulse micropill, its basic structure is from inside to outside of quick-release pill core containing medicine, alkaline layer and hysteresis layer respectively, in which the hysteresis layer contains polyacrylic resin iii, however, the pulse micropill prepared by said technology can release medicine completely after 3 hr from time lag, and its medicine release rate is slow.
The pulse release oral preparation disclosed in CN1488332A and the preparation method thereof, and the oral gastric floating system disclosed in CN1261533A are all techniques for preparing tablet cores or particles with different time lags by multiple coatings.
CN1404389a discloses a dosage form consisting of one or more beads, each bead containing at least two coating films, except for the fast-release beads.
The preparation of the preparation in the patent has the defects of certain process difficulty and poor process stability.
Disclosure of Invention
The invention aims to overcome the defects of the technology and provide a gastric floating release type sustained release preparation which is only required to be taken once a day, and the weight of the sustained release tablet is smaller than the generated buoyancy after the sustained release tablet contacts gastric juice, so that the sustained release tablet floats on the upper part of the gastric juice rapidly, the floating time can last for 3-6 hours, and the sustained release tablet has larger expansion size. The gastric residence time of the composition is prolonged by combining the gastric floating technology and size exclusion, so that the medicine is better absorbed at the absorption part, and the individuation difference under different physiological conditions is reduced by the characteristics of stronger gel strength and dissolution characteristics of the framework material. Meanwhile, the auxiliary materials used by the invention are easy to obtain, the production process is simple and easy to operate, and the invention is suitable for industrial production.
The zolpidem tartrate gastric-floating sustained release tablet disclosed by the invention comprises the following components:
zolpidem tartrate 0.6-1.8%,
30 to 80 percent of swelling agent,
5 to 40 percent of sustained and controlled release material,
5 to 40 percent of filling agent,
0.5 to 10 percent of pore-forming agent,
0.4 to 3 percent of lubricant.
Preferably, the zolpidem tartrate gastric-floating sustained release tablet comprises the following components:
zolpidem tartrate 0.6-1.8%,
40 to 70 percent of swelling agent,
10 to 30 percent of sustained and controlled release material,
5 to 35 percent of filling agent,
2 to 8 percent of pore-forming agent,
1 to 2 percent of lubricant.
In order to achieve the technical aim, the zolpidem tartrate gastric-floating sustained-release tablet comprises an active ingredient, a framework material, a swelling agent and an excipient.
Wherein the active ingredient is zolpidem tartrate and pharmaceutically acceptable salts, solvates, hydrates or complexes thereof;
the framework material is any one or the combination of a plurality of hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic resin and derivatives thereof;
wherein the active ingredient accounts for 0.6-1.8% of the total weight of the sustained release tablet; the framework material accounts for 5% -40% of the total weight of the sustained-release tablet; the swelling agent accounts for 30-80% of the total weight of the sustained release tablet, and the balance is filler, pore-forming agent and lubricant.
In one embodiment, the skeleton material is hypromellose or hypromellose, and the content of the skeleton material is 5% -40% of the total weight of the sustained release tablet, preferably 5% -25%.
In other embodiments, the matrix material is an acrylic resin and its derivatives, and the content of the matrix material is 5% -35% of the total weight of the sustained release tablet, preferably 5% -20%.
For solid oral sustained release preparations, the in vivo environment has a certain influence on the release and absorption of the medicine. The early research of the invention shows that the dissolution of the zolpidem tartrate quick-release tablet is influenced by the pH value (intragastric environment) and the rotating speed of a paddle method (gastric motility).
In a preferred embodiment of the present invention, the skeleton material is a combination of hypromellose, acrylic resin, and derivatives thereof, and accounts for 10% -40% of the total weight of the pharmaceutical composition.
Wherein the weight percentage of the hypromellose and/or the hypromellose to the acrylic resin and the derivatives thereof is 9:1 to 1:2, preferably 3:1 to 1:1. Because the framework material combination has the characteristics of stronger gel strength and dissolution characteristic, the aim of generating stable treatment effect under different physiological conditions (different gastric motility and pH value) can be fulfilled.
Specifically, the acrylic resin and the derivative thereof are copolymers formed by any one or more monomers of methacrylic acid, methyl methacrylate, methacrylic acid, butyl methacrylate, ethyl acrylate and trimethylaminoethyl methacrylate chloride; or from evonik industries under the trade names e.g., E100, l100\s100, RL100\rs100, L30D-55, RL30d\rs30D, etc. The molecular weight of the hypromellose or the hypromellose is 1×10 5 ～1×10 7 Preferably having a molecular weight of 5X 10 5 ～2×10 6 。
The swelling agent in the zolpidem tartrate gastric-floating sustained-release tablet can expand to a plurality of times of the original volume after absorbing water in gastric juice, thereby achieving the purpose of size exclusion and prolonging the gastric retention time of the oral solid preparation. At the same time, swelling agent gelation affects drug release.
In one embodiment, the swelling agent adopted by the invention is polyethylene oxide, and the content of the swelling agent is 20-70% of the total weight of the sustained release tablet; preferably 20% -60%; the polyethylene oxide has a molecular weight of 1×10 5 ～1×10 7 。
In some embodiments of the invention, the swelling agent is a combination of different polyethylene oxides, in particularIs a combination of high molecular weight polyethylene oxide and low molecular weight polyethylene oxide. Wherein the high molecular weight polyethylene oxide has a molecular weight of 2X 10 6 ～7×10 6 The molecular weight of the low molecular weight polyethylene oxide is 1×10 5 ～2×10 6 The weight percent of high molecular weight to low molecular weight polyethylene oxide is from 5:1 to 1:5, preferably from 4:1 to 1:2.
In some embodiments of the invention, the swelling agent contains, in addition to the polyethylene oxide, crosslinked polyvinylpyrrolidone, also known as crospovidone. Wherein, the cross-linked polyvinylpyrrolidone accounts for 5 to 40 percent of the total weight of the sustained release tablet, preferably 10 to 30 percent.
In some embodiments of the present invention, the swelling agent is a combination of crosslinked polyvinylpyrrolidone and polyethylene oxide, accounting for 30% -70% of the total weight of the sustained release tablet, wherein the weight percentage of crosslinked polyvinylpyrrolidone to polyethylene oxide is 1:5 to 4:1, preferably 1:4 to 2:1.
The lubricant accounts for 0.4-3% of the total weight of the pharmaceutical composition, and comprises at least one of magnesium stearate, sodium stearate fumarate, talcum powder, glyceryl behenate, glyceryl monostearate, glyceryl distearate and silicon dioxide. The filler accounts for 5-40% of the total weight of the pharmaceutical composition, and comprises at least one of starch, lactose, mannitol, sorbitol, pregelatinized starch, microcrystalline cellulose and calcium hydrophosphate. The pore-forming agent accounts for 0.5-10% of the total weight of the pharmaceutical composition, and comprises at least one of sodium dodecyl sulfate, polysorbate 80, polyethylene glycol, carbonate, bicarbonate and polyvinylpyrrolidone.
The preparation method of the zolpidem tartrate gastric-floating sustained-release tablet comprises the following two methods:
1) Wet granulation: premixing zolpidem tartrate and part of auxiliary materials except magnesium stearate in a high-shear granulating pot, and performing wet granulation by taking water or ethanol water solutions with different proportions as binders; mixing the particles with the rest components; finally, the tablets are pressed on a tablet press, and the pressed tablets can be coated by a coating machine. The particle size of one or more components can be controlled by at least one of sieving and crushing processes in the preparation process; the size and fluidity of the granules can also be controlled by controlling the amount of binder, the ratio of ethanol to water, the components of the granulation and the time of the granulation.
2) Powder direct compression method: the pharmaceutical composition is dry-mixed in a mixing drum and then compressed into tablets on a tablet press, and the compressed tablets can be coated by a coating machine. To improve the uniformity of the product, the components may be added in stages and mixed uniformly. For example, the drug may be dry blended with one or more matrix materials and then mixed with the remaining materials (swelling agents, fillers, lubricants, etc.). The particle size of one or more components can be controlled by at least one of sieving and pulverizing.
Compared with the common zolpidem tartrate oral quick-release tablet or slow-release matrix tablet, the invention has the following beneficial effects:
the invention prolongs the gastric retention time of the zolpidem tartrate gastric-floating sustained-release tablet by combining the gastric floating technology and size exclusion, so that the sustained-release tablet is retained in the stomach of a patient for 4-5 hours after oral administration, compared with the common sustained-release dosage form, the zolpidem tartrate gastric-floating sustained-release tablet can more effectively control the blood concentration in a stable and effective range in the normal sleeping time after the administration of insomnia patients, so that the medicine is better absorbed at the absorption part, has higher bioavailability in the body, obviously reduces possible side effects and obviously improves the use safety of the medicine.
Drawings
FIG. 1 shows the results of elution and release in examples 1 to 4 and comparative examples 1 to 2
FIG. 2 shows the results of elution and release in examples 5 to 8 and comparative examples 3 to 4
Detailed Description
The present invention is further illustrated below with reference to specific examples, which are to be construed as merely illustrative of the invention and not limiting of its scope, as various equivalents thereof will suggest themselves to those skilled in the art upon reading the present invention, as defined in the appended claims.
Example 1
The zolpidem gastric floating sustained release tablet comprises the following components:
Figure BDA0003404673710000051
Figure BDA0003404673710000061
the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent and the pore-forming agent with the prescribed amount are prepared into particles by a wet granulation process by taking water (the use amount is 35 percent of the weight of the mixture) as a solvent, and then the particles are pressed into tablets and coated after being added with the lubricant and uniformly mixed.
Example 2
The zolpidem gastric floating sustained release tablet comprises the following components:
Figure BDA0003404673710000062
the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent and the pore-forming agent with the prescribed amount are prepared into particles by a wet granulation process by taking water (the use amount is 35 percent of the weight of the mixture) as a solvent, and then the particles are pressed into tablets and coated after being added with the lubricant and uniformly mixed.
Example 3
The zolpidem gastric floating sustained release tablet comprises the following components:
Figure BDA0003404673710000063
Figure BDA0003404673710000071
the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent and the pore-forming agent with the prescribed amount are prepared into particles by a wet granulation process by taking water (the use amount is 35 percent of the weight of the mixture) as a solvent, and then the particles are pressed into tablets and coated after being added with the lubricant and uniformly mixed.
Example 4
The zolpidem gastric floating sustained release tablet comprises the following components:
Figure BDA0003404673710000072
the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent and the pore-forming agent with the prescribed amount are prepared into particles by a wet granulation process by taking water (the use amount is 35 percent of the weight of the mixture) as a solvent, and then the particles are pressed into tablets and coated after being added with the lubricant and uniformly mixed.
Example 5
The zolpidem gastric floating sustained release tablet comprises the following components:
Figure BDA0003404673710000073
Figure BDA0003404673710000081
the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent, the pore-forming agent and the lubricant with the prescription amount are dry-mixed in a mixing barrel, and then tableted and coated.
Example 6
The zolpidem gastric floating sustained release tablet comprises the following components:
Figure BDA0003404673710000082
the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent, the pore-forming agent and the lubricant with the prescription amount are dry-mixed in a mixing barrel, and then tableted and coated.
Example 7
The zolpidem gastric floating sustained release tablet comprises the following components:
Figure BDA0003404673710000091
the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent, the pore-forming agent and the lubricant with the prescription amount are dry-mixed in a mixing barrel, and then tableted and coated.
Example 8
The zolpidem gastric floating sustained release tablet comprises the following components:
Figure BDA0003404673710000092
the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent, the pore-forming agent and the lubricant with the prescription amount are dry-mixed in a mixing barrel, and then tableted and coated.
Comparative example 1
The composition of the zolpidem gastric-floating sustained-release tablet of comparative example 1 is as follows:
Figure BDA0003404673710000101
the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent and the pore-forming agent with the prescribed amount are prepared into particles by a wet granulation process by taking water (the use amount is 35 percent of the weight of the mixture) as a solvent, and then the particles are pressed into tablets and coated after being added with the lubricant and uniformly mixed.
Comparative example 2
The composition of the zolpidem gastric-floating sustained-release tablet of comparative example 2 is as follows:
Figure BDA0003404673710000102
Figure BDA0003404673710000111
the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent and the pore-forming agent with the prescribed amount are prepared into particles by a wet granulation process by taking water (the use amount is 35 percent of the weight of the mixture) as a solvent, and then the particles are pressed into tablets and coated after being added with the lubricant and uniformly mixed.
Comparative example 3
The composition of the zolpidem gastric-floating sustained-release tablet of comparative example 3 is as follows:
Figure BDA0003404673710000112
Figure BDA0003404673710000121
the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent, the pore-forming agent and the lubricant with the prescription amount are dry-mixed in a mixing barrel, and then tableted and coated.
Comparative example 4
The composition of the zolpidem gastric-floating sustained-release tablet of comparative example 4 is as follows:
Figure BDA0003404673710000122
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the preparation method comprises the following steps: the zolpidem tartrate, the slow-release material, the swelling agent, the filling agent, the pore-forming agent and the lubricant with the prescription amount are dry-mixed in a mixing barrel, and then tableted and coated.
Dissolution test
According to the method of a drug dissolution device of dissolution method II (slurry method) of Chinese pharmacopoeia (2020 edition), examples 1 to 8, comparative examples 1 to 4, zolpidem tartrate gastric-floating sustained-release tablets were measured for drug dissolution at 30, 60, 120, 180, 210, 240, 360, 480 minutes at 37℃and a paddle rotation speed of 100rpm in 900ml of 0.1M hydrochloric acid dissolution medium, and the results are shown in tables 1 and 2.
Table 1: examples 1-4, comparative examples 1-2 release results
Figure BDA0003404673710000131
As can be seen from Table 1, examples 1-4 can be released slowly within 5 hours, and have longer residence time in stomach and better slow release effect; whereas comparative examples 1 and 2 almost completed release within 2 hours, the slow release effect was poor.
Table 2: examples 5 to 8, comparative examples 3 to 4 release results
Figure BDA0003404673710000132
As can be seen from Table 2, examples 5-8 can be released slowly within 4 hours, and have longer residence time in stomach and better slow release effect; whereas comparative examples 3 and 4 almost completed release within 2 hours, the slow release effect was poor.

Claims (10)

1. The zolpidem tartrate gastric-floating sustained-release tablet is characterized by comprising the following components:
zolpidem tartrate 0.6-1.8%
30 to 80 percent of swelling agent
10 to 40 percent of sustained and controlled release material
5 to 40 percent of filling agent
0.5 to 10 percent of pore-forming agent
0.4 to 3 percent of lubricant.
2. The zolpidem tartrate gastric-floating sustained-release tablet of claim 1, wherein the zolpidem tartrate gastric-floating sustained-release tablet comprises the following components:
zolpidem tartrate 0.6-1.8%
40 to 70 percent of swelling agent
20 to 30 percent of sustained and controlled release material
5 to 35 percent of filling agent
Pore-forming agent 2-8%
1 to 2 percent of lubricant.
3. The zolpidem tartrate gastric-floating sustained-release tablet of claim 1 or 2, wherein said swelling agent is polyethylene oxide, and the content of said polyethylene oxide is 6% -64% of the total weight of said sustained-release tablet; the polyethylene oxide has a molecular weight of 1×10 5 ～1×10 7 。
4. The zolpidem tartrate gastric-floating sustained release tablet of claim 3, wherein said polyethylene oxide is a combination of high molecular weight and low molecular weight polyethylene oxides, said high molecular weight polyethylene oxide having a molecular weight of 2 x 10 6 ～7×10 6 The molecular weight of the low molecular weight polyethylene oxide is 1×10 5 ～2×10 6 The weight percent of the high molecular weight to low molecular weight polyethylene oxide is from 5:1 to 1:5.
5. The zolpidem tartrate gastric-floating sustained-release tablet of claim 1 or 2, wherein said swelling agent is crospovidone, and wherein the content of crospovidone is 6% -64% of the total weight of said sustained-release tablet.
6. The zolpidem tartrate gastric-floating sustained-release tablet of claim 1 or 2, wherein the swelling agent is a combination of crosslinked polyvinylpyrrolidone and polyethylene oxide, the combined content of crosslinked polyvinylpyrrolidone and polyethylene oxide being 30-80% of the total weight of the sustained-release tablet, wherein the weight percentage of crosslinked polyvinylpyrrolidone and polyethylene oxide is 1:4 to 4:1.
7. The zolpidem tartrate gastric-floating sustained-release tablet of claim 1 or 2, wherein the sustained-release material comprises 10% to 40% by weight of the total weight of the pharmaceutical composition, and the sustained-release material comprises a combination of hyprolose, a series of copolymers of hypromellose and acrylic resin, hypromellose and/or hypromellose and acrylic resin and derivatives thereof, wherein the weight ratio of the total weight of hypromellose or hypromellose to the acrylic resin and derivatives thereof is from 9:1 to 1:2.
8. The zolpidem tartrate gastric-floating sustained release tablet of claim 7, wherein said acrylic resin and derivatives thereof are selected from the group consisting of the ulide series of sustained and controlled release materials, said hypromellose or hydroxypropyl cellulose having a molecular weight of 1 x 10 5 ～1×10 7 。
9. The zolpidem tartrate gastric-floating sustained-release tablet of claim 1 or 2, wherein the lubricant is 0.4% to 3% of the total weight of the pharmaceutical composition, and the lubricant is at least one of magnesium stearate, sodium stearate fumarate, talc, glyceryl behenate, glyceryl monostearate, glyceryl distearate and silica; the filler accounts for 5-40% of the total weight of the pharmaceutical composition, and is at least one of starch, lactose, mannitol, sorbitol, pregelatinized starch, microcrystalline cellulose and calcium hydrophosphate; the pore-forming agent accounts for 0.5-4% of the total weight of the pharmaceutical composition, and is at least one of sodium dodecyl sulfate, polysorbate 80, polyethylene glycol, carbonate, bicarbonate and polyvinylpyrrolidone.
10. The method for preparing zolpidem tartrate gastric-floating sustained-release tablets of claim 1 or 2, wherein the preparation method is a wet granulation method or a powder direct compression method;
wet granulation:
(1) Premixing zolpidem tartrate and part of auxiliary materials except magnesium stearate in a high-shear granulating pot, and performing wet granulation by taking water or ethanol water solutions with different proportions as binders;
(2) Mixing the particles with the rest components; finally, pressing the mixture into tablets on a tablet press, wherein the pressed tablets can be coated by a coating machine;
powder direct compression method:
(1) The pharmaceutical composition is dry-mixed in a mixing drum and then compressed into tablets on a tablet press, and the compressed tablets can be coated by a coating machine.
CN202111506669.4A 2021-12-10 2021-12-10 Zolpidem tartrate gastric-floating release tablet and preparation method thereof Pending CN116251069A (en)

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