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CN116172976A - Cyclobenzaprine hydrochloride sustained-release capsule and preparation method thereof - Google Patents

Cyclobenzaprine hydrochloride sustained-release capsule and preparation method thereof Download PDF

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Publication number
CN116172976A
CN116172976A CN202211691406.XA CN202211691406A CN116172976A CN 116172976 A CN116172976 A CN 116172976A CN 202211691406 A CN202211691406 A CN 202211691406A CN 116172976 A CN116172976 A CN 116172976A
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release
sustained
cyclobenzaprine hydrochloride
capsule
coating
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龚健
马甜甜
徐彦
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Nantong Lianya Pharmaceutical Co ltd
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Nantong Lianya Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • General Chemical & Material Sciences (AREA)
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Abstract

The invention relates to a cyclobenzaprine hydrochloride sustained-release capsule, the content of the sustained-release capsule comprises sustained-release coated pellets, the sustained-release coated pellets are prepared from blank pellet cores and a drug-containing sustained-release coating layer, the drug-containing sustained-release coating layer comprises a cyclobenzaprine hydrochloride Lin Hehuan release material, and a coating solvent used in the coating process of the sustained-release coated pellets does not contain ethanol or water. The cyclobenzaprine hydrochloride sustained-release capsule prepared by the invention not only has the in-vitro release degree similar to that of the original preparation, but also has good chemical stability, and ensures the safety and effectiveness of clinical medication.

Description

Cyclobenzaprine hydrochloride sustained-release capsule and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a cyclobenzaprine hydrochloride sustained-release capsule.
Background
Cyclobenzaprine hydrochloride, known as 5- (3-dimethylaminopropylene) dibenzo [ a, e ] cycloheptatriene hydrochloride, is a tricyclic muscle relaxant developed by merck corporation and approved for sale in more than ten countries such as the united states in the 80 s of the 20 th century, and is clinically used mainly for the treatment of skeletal muscle system discomfort or muscle spasms (including pain, tenderness, movement limitation, daily activity limitation, etc.) associated with pain symptoms. However, due to the short half-life period of cyclobenzaprine hydrochloride in organisms, the common dosage form needs to be taken 3 times per day, and the administration is frequent, so that the compliance of patients in administration is affected.
The cyclobenzaprine hydrochloride sustained-release pellet capsule is a sustained-release preparation which is developed successfully by Anesta pharmaceutical company in the United states first, and is approved to be marketed in the United states in month 2 of 2007, and the product name is
Figure BDA0004021241580000011
The market specification comprises 15mg and 30mg, the blood concentration can be maintained for 24 hours only by taking the medicine 1 time a day, the sustained-release preparation obviously improves the compliance of the patient in taking the medicine, and the imitation development of the cyclobenzaprine hydrochloride sustained-release pellet capsule has good market prospect.
The prior art CN114432266A discloses a cyclobenzaprine hydrochloride sustained-release capsule, the content of the capsule comprises sustained-release coated pellets and a lubricant, the sustained-release coated pellets comprise cyclobenzaprine hydrochloride, blank pellet cores, a sustained-release material and a stabilizer, a coating solvent used in the process of coating the sustained-release pellets is ethanol, but researches show that the sustained-release capsule obtained by using the ethanol as the coating solvent easily has the problem of inconsistent in-vitro release degree with the original preparation. In addition, if an aqueous solvent is added during the preparation of the coating solution, the water of the sustained-release pellets is easy to remain in the drug-containing coating layer after the sustained-release pellets are coated by a fluidized bed, which is not beneficial to the chemical stability of the active ingredients in long-term storage.
At present, the specific external release is consistent with the original development agent, the chemical stability is good, and the cyclobenzaprine hydrochloride sustained-release capsule imitation pharmacy without a stabilizer is not reported.
Disclosure of Invention
The invention aims to provide the cyclobenzaprine hydrochloride sustained-release capsule which has the advantages of similar in-vitro release to the original preparation, good chemical stability and simple preparation process.
In order to solve the technical problems, the first aspect of the invention provides a cyclobenzaprine hydrochloride sustained-release capsule, the content of the sustained-release capsule comprises sustained-release coated pellets, the sustained-release coated pellets are prepared from blank pellet cores and a drug-containing sustained-release coating layer, the drug-containing sustained-release coating layer comprises a cyclobenzaprine hydrochloride Lin Hehuan release material, and a coating solvent used in the coating process of the sustained-release coated pellets does not contain ethanol or water.
Preferably, the coating solvent is selected from one or more of isopropanol, n-propanol, n-butanol and tert-butanol. More preferably, the coating solvent is selected from one or more of isopropyl alcohol and n-propyl alcohol. Further preferably, the coating solvent is isopropyl alcohol.
Preferably, the slow release material is selected from one or more of ethyl cellulose and acrylic resin. More preferably, the slow release material is ethylcellulose. Further preferably, the slow release material has a viscosity of 18-24mpa.s and is ethylcellulose.
Preferably, the blank pellet core is a sucrose pellet core.
Preferably, the contents of the extended release capsule further comprise a lubricant.
Preferably, the lubricant is selected from one or more of magnesium stearate, calcium stearate, stearic acid, silica, talc and glyceryl behenate. More preferably, the lubricant is selected from one or more of magnesium stearate, silica and talc. Further preferably, the lubricant is talc.
Preferably, the slow release coating layer further comprises a plasticizer.
Preferably, the plasticizer is selected from one or more of triethyl citrate, dibutyl phthalate or glyceryl triacetate. More preferably, the plasticizer is selected from one or more of triethyl citrate or dibutyl phthalate. Further preferably, the plasticizer is triethyl citrate.
Preferably, the coating layer does not contain a stabilizer. More preferably, the stabilizer is one or more selected from antioxidant, edetic acid and its salts, glyceryl monostearate. Further preferably, the antioxidant is selected from one or more of vitamin C, vitamin E and sulfite, and the edetate is selected from one or more of disodium edetate, dipotassium edetate, calcium disodium edetate, sodium edetate and trisodium edetate.
Preferably, the cyclobenzaprine hydrochloride Lin Chongliang accounts for 15-35% of the content of the sustained release capsule. More preferably, the cyclobenzaprine hydrochloride Lin Chongliang accounts for 18-30% of the content of the sustained release capsule. Further preferably, the cyclobenzaprine hydrochloride Lin Chongliang accounts for 21.2-26.4% of the content of the sustained release capsule.
Preferably, the weight of the blank pill core accounts for 20-45% of the content of the slow release capsule. More preferably, the weight of the blank pellet core accounts for 25-40% of the content of the slow release capsule. Further preferably, the weight of the blank pellet core accounts for 33-35.4% of the content of the slow release capsule.
Preferably, the weight of the slow release material accounts for 30-55% of the content of the slow release capsule. More preferably, the weight of the slow release material accounts for 30-45% of the content of the slow release capsule. Further preferably, the weight of the slow release material accounts for 35.4-39.6% of the content of the slow release capsule.
Preferably, the slow release material in the coating liquid accounts for 2-10% of the weight of the coating liquid; more preferably, the slow release material in the coating liquid accounts for 4-8% of the weight of the coating liquid; further preferably, the slow release material in the coating liquid accounts for 6% of the weight of the coating liquid.
Preferably, the lubricant is 0.1-2% by weight of the contents of the sustained release capsule. More preferably, the lubricant comprises 0.3-1.5% by weight of the contents of the sustained release capsule. Further preferably, the lubricant comprises 0.5-1% by weight of the contents of the sustained release capsule.
Preferably, the plasticizer comprises 3-10% by weight of the contents of the sustained release capsule. More preferably, the plasticizer comprises 5-8% by weight of the contents of the extended release capsule. Further preferably, the plasticizer comprises 7% by weight of the contents of the extended release capsule.
Preferably, the slow release capsule content comprises the following components in percentage by weight: 26.4% cyclobenzaprine hydrochloride, 33% sucrose pellet core, 39.6% ethylcellulose and 1% talcum powder.
Preferably, the slow release capsule content comprises the following components in percentage by weight: 21.2% cyclobenzaprine hydrochloride, 35.4% sucrose pellet core, 35.4% ethylcellulose, 7% triethyl citrate and 1% talcum powder.
Preferably, the slow release capsule content comprises the following components in percentage by weight: 18.6% cyclobenzaprine hydrochloride, 24.7% sucrose pellet core, 55.7% ethylcellulose and 1% talcum powder.
Preferably, the cyclobenzaprine hydrochloride sustained-release capsule has a factor f similar to that of Amrix which is the original preparation 2 The value is greater than 50. More preferably, the cyclobenzaprine hydrochloride sustained-release capsule has a factor f similar to that of Amrix which is the original preparation 2 The value is greater than 55. Further preferably, the cyclobenzaprine hydrochloride sustained-release capsule has a factor f similar to that of Amrix which is the original preparation 2 The value is greater than 60.
Preferably, the total content of impurities of the cyclobenzaprine hydrochloride sustained-release capsule is less than 0.05% when the capsule is placed for 1 month at 40 ℃ and RH 75%. More preferably, the total content of impurities of the cyclobenzaprine hydrochloride sustained-release capsule is less than 0.05% when the capsule is placed for 2 months at 40 ℃ and RH 75%. Further preferably, the total content of impurities of the cyclobenzaprine hydrochloride sustained-release capsule is less than 0.05% when the capsule is placed for 3 months at 40 ℃ and RH 75%.
The second aspect of the invention provides a preparation method of the cyclobenzaprine hydrochloride sustained-release capsule, which comprises the following steps:
(1) Dissolving the cyclobenzaprine hydrochloride, the slow release material and the optional plasticizer with the prescription amount in a coating solvent to prepare coating liquid;
(2) Slowly spraying the coating liquid prepared in the step (1) on blank pellet cores in a fluidized bed coating machine to prepare slow-release coated pellets;
(3) Mixing the slow-release coated micropellets with optional lubricant, and encapsulating to obtain the final product;
the coating solvent used in step (1) does not contain ethanol or water.
Preferably, the coating solvent is selected from one or more of isopropanol, n-propanol, n-butanol and tert-butanol. More preferably, the coating solvent is selected from one or more of isopropyl alcohol and n-propyl alcohol. Further preferably, the coating solvent is isopropyl alcohol.
Preferably, the parameters of the fluidized bed coating in the step (2) are as follows: the air inlet temperature is 35-45 ℃, the material temperature is 30-40 ℃, the air outlet temperature is 25-35 ℃, the atomization pressure is 1.0-3.0bar, the air quantity is 100-300cfm, the humidity is 10-40%, and the flow rate is 5-30g/min.
More preferably, the parameters of the fluidized bed coating in the step (2) are as follows: the air inlet temperature is 40 ℃, the material temperature is 32 ℃, the air outlet temperature is 31 ℃, the atomization pressure is 1.5bar, the air quantity is 100cfm, the humidity is 20%, and the flow rate is 21g/min.
The third aspect of the invention provides the application of the cyclobenzaprine hydrochloride sustained release capsule in medicines for relieving local muscle spasms and accompanying symptoms.
Preferably, the concomitant symptoms are pain, tenderness, restricted activity, and restricted activities of daily living.
The fourth aspect of the invention provides an application of the cyclobenzaprine hydrochloride sustained-release capsule in preparing a muscle relaxant.
In a fifth aspect, the present invention provides the use of a coating solvent, which does not contain ethanol or water, for improving the in vitro release and/or chemical stability of the cyclobenzaprine hydrochloride sustained release capsules described above.
Furthermore, the invention provides application of the coating solvent in improving the in-vitro release degree and chemical stability of the cyclobenzaprine hydrochloride sustained-release capsule, wherein the coating solvent does not contain ethanol or water.
Preferably, the coating solvent is selected from one or more of isopropanol, n-propanol, n-butanol and tert-butanol. More preferably, the coating solvent is selected from one or more of isopropyl alcohol and n-propyl alcohol. Further preferably, the coating solvent is isopropyl alcohol.
Preferably, the in-vitro release degree of the improved cyclobenzaprine hydrochloride sustained-release capsule is the similarity factor f of the cyclobenzaprine hydrochloride sustained-release capsule and the original development agent Amrix 2 The value is greater than 50. More preferably, the cyclobenzaprine hydrochloride sustained-release capsule has a factor f similar to that of Amrix which is the original preparation 2 The value is greater than 55. Further preferably, the cyclobenzaprine hydrochloride sustained-release capsuleSimilarity factor f to Amrix, the original developer 2 The value is greater than 60.
Preferably, the chemical stability of the improved cyclobenzaprine hydrochloride sustained-release capsule is that the total content of impurities when the cyclobenzaprine hydrochloride sustained-release capsule is placed for 1 month under the conditions of 40 ℃ and RH75 percent is less than 0.05 percent. More preferably, the total content of impurities of the cyclobenzaprine hydrochloride sustained-release capsule is less than 0.05% when the capsule is placed for 2 months at 40 ℃ and RH 75%. Further preferably, the total content of impurities of the cyclobenzaprine hydrochloride sustained-release capsule is less than 0.05% when the capsule is placed for 3 months at 40 ℃ and RH 75%.
The sixth aspect of the invention provides an application of a coating solution in improving the in-vitro release rate and/or chemical stability of the cyclobenzaprine hydrochloride sustained-release capsule, wherein the coating solution comprises cyclobenzaprine hydrochloride, a sustained-release material and a coating solvent, and the coating solvent does not contain ethanol or water.
Preferably, the invention provides application of the coating liquid in improving the in-vitro release rate and chemical stability of the cyclobenzaprine hydrochloride sustained-release capsule.
Preferably, the coating solvent is selected from one or more of isopropanol, n-propanol, n-butanol and tert-butanol. More preferably, the coating solvent is selected from one or more of isopropyl alcohol and n-propyl alcohol. Further preferably, the coating solvent is isopropyl alcohol.
Preferably, the coating solution does not contain a stabilizer. More preferably, the stabilizer is one or more selected from antioxidant, edetic acid and its salts, glyceryl monostearate. Further preferably, the antioxidant is selected from one or more of vitamin C, vitamin E and sulfite, and the edetate is selected from one or more of disodium edetate, dipotassium edetate, calcium disodium edetate, sodium edetate and trisodium edetate.
Preferably, the cyclobenzaprine hydrochloride Lin Chongliang accounts for 15-35% of the content of the sustained release capsule. More preferably, the cyclobenzaprine hydrochloride Lin Chongliang accounts for 18-30% of the content of the sustained release capsule. Further preferably, the cyclobenzaprine hydrochloride Lin Chongliang accounts for 21.2-26.4% of the content of the sustained release capsule.
Preferably, the weight of the slow release material accounts for 30-55% of the content of the slow release capsule. More preferably, the weight of the slow release material accounts for 30-45% of the content of the slow release capsule. Further preferably, the weight of the slow release material accounts for 35.4-39.6% of the content of the slow release capsule.
Preferably, the in-vitro release degree of the improved cyclobenzaprine hydrochloride sustained-release capsule is the similarity factor f of the cyclobenzaprine hydrochloride sustained-release capsule and the original development agent Amrix 2 The value is greater than 50. More preferably, the cyclobenzaprine hydrochloride sustained-release capsule has a factor f similar to that of Amrix which is the original preparation 2 The value is greater than 55. Further preferably, the cyclobenzaprine hydrochloride sustained-release capsule has a factor f similar to that of Amrix which is the original preparation 2 The value is greater than 60.
Preferably, the chemical stability of the improved cyclobenzaprine hydrochloride sustained-release capsule is that the total content of impurities when the cyclobenzaprine hydrochloride sustained-release capsule is placed for 1 month under the conditions of 40 ℃ and RH75 percent is less than 0.05 percent. More preferably, the total content of impurities of the cyclobenzaprine hydrochloride sustained-release capsule is less than 0.05% when the capsule is placed for 2 months at 40 ℃ and RH 75%. Further preferably, the total content of impurities of the cyclobenzaprine hydrochloride sustained-release capsule is less than 0.05% when the capsule is placed for 3 months at 40 ℃ and RH 75%.
The invention has the technical effects that:
1. according to the invention, the specific organic solvent (such as isopropanol), cyclobenzaprine hydrochloride and a slow-release material are directly wrapped in a blank pill core, so that the prepared cyclobenzaprine hydrochloride slow-release capsule has the in-vitro release degree similar to that of the original preparation, has good chemical stability under the condition of not containing a stabilizer, and the total impurity amount is still less than 0.05% after long-term placement under the conditions of 40 ℃ and RH75%, thereby ensuring the safety and effectiveness of clinical medication.
2. The preparation process of the cyclobenzaprine hydrochloride sustained-release capsule provided by the invention adopts one-step coating of active ingredients and sustained-release materials, and has the advantages of simple production process and short process time.
Detailed Description
The following describes in detail the examples of the present invention, which are implemented on the premise of the technical solution of the present invention, and detailed embodiments and specific operation procedures are given, but the scope of protection of the present invention is not limited to the following examples.
Test example 1 influence of coating solvent on in vitro Release degree of cyclobenzaprine hydrochloride sustained-release capsule
1. Test method
1.1 preparation of sustained Release Capsule
(1) Prescription of prescription
The formulations of examples 1-3 of the present invention are shown in the following table (unit dose 30 mg).
Figure BDA0004021241580000061
a: and volatilizing in the coating process.
The formulations of comparative examples 1 to 3 according to the present invention are shown in the following table (unit dose: 30 mg).
Figure BDA0004021241580000062
Figure BDA0004021241580000071
a: and volatilizing in the coating process.
(2) Preparation process
The preparation methods of examples 1-3 and comparative examples 1-3 were as follows: (1) Adding the cyclobenzaprine hydrochloride, ethyl cellulose and optionally triethyl citrate with the prescribed amount into a coating solvent (isopropanol or ethanol), wherein the weight percentage of the ethyl cellulose in the coating liquid is 6%; (2) Placing a prescribed amount of sucrose pellets in a fluidized bed coating machine; (3) setting fluidized bed package parameters: the air inlet temperature is 40 ℃, the material temperature is 32 ℃, the air outlet temperature is 31 ℃, the atomization pressure is 1.5bar, the air quantity is 100cfm, the humidity is 20%, the flow rate is 21g/min, and the coating liquid prepared in the step (1) is slowly sprayed into a fluidized bed, so that a drug-containing slow-release layer is coated on a sucrose pill core; (4) Discharging after coating, mixing sucrose pill core coated with drug-containing slow release layer with pulvis Talci, and encapsulating (capsule unit dose is 30 mg).
1.2 in vitro Release detection
The cyclobenzaprine hydrochloride sustained release capsules prepared in examples 1-2 and comparative examples 1-3 and the original ground reference formulation Amrix (30 mg specification) were subjected to in vitro release test, and the specific release measurement method is as follows: the paddle method, rotating at 50rpm, test solution 0.1N hydrochloric acid, 900ml, test temperature 37.+ -. 0.5 ℃, measured in vitro release at 1,2, 4, 8, 12 and 16 hours, calculated cumulative percent release at each time point.
Similarity factor (f) 2 ) The method is a parameter for measuring the similarity of two dissolution curves, and the calculation formula is as follows:
f 2 ＝50log[[1+1/nΣ(R t -T t ) 2 ] -0.5 ×100]
wherein R is t Cumulative percent release for the reference formulation at time t; t (T) t Cumulative percent drug release for the test formulation at time t; n is the number of sampling points. F when the two release curves completely coincide 2 100; f when the difference between the two curves increases 2 The value decreases. General rule f 2 The value of 50-100 can be considered that the two formulations have no difference in drug release under the same drug release condition.
2. Test results
The results of the in vitro release rates of the sustained release capsules of examples 1 to 2 and comparative examples 1 to 3 at different time points are shown in Table 1 below.
TABLE 1 in vitro Release degree (%)
Time Example 1 Example 2 Comparative example 1 Comparative example 2 Comparative example 3 Reference formulation
1h 15 17 93 92 24 7
2h 25 26 93 92 33 28
4h 45 43 94 93 55 52
8h 67 72 93 93 73 70
12h 73 81 94 93 79 78
16h 76 86 94 94 84 83
f2 61 61 16 16 56 —
From the results of the in vitro release rates of the above table 1, it is evident that the comparative examples 1 to 2 using ethanol as the coating solvent have a release rate of less than 50 as compared with the reference formulation, which indicates that the in vitro dissolution behavior of comparative examples 1 and 2 is dissimilar to that of the reference formulation, while the comparative examples 1 to 2 using isopropanol as the coating solvent have a similarity factor of more than 60, which indicates that the in vitro release rate of the cyclobenzaprine hydrochloride sustained release capsule can be significantly improved after using isopropanol instead of ethanol.
Test example 2 influence of coating solvent on impurity content of cyclobenzaprine hydrochloride sustained-release capsule
1. Test method
The cyclobenzaprine hydrochloride sustained release capsules of examples 1-3 and comparative example 3 were placed at 40 ℃ and 75% RH, sampled at months 0,1,2 and 3, respectively, and examined for the generation of total impurities in the sustained release capsules at different sampling times, and the total weight percent (%) of the impurities in the active drug was calculated by self-contrast.
The sample treatment method is as follows: weighing a proper amount of cyclobenzaprine hydrochloride sustained release capsule content, placing into a volumetric flask, adding methanol with volume of 60% of the volumetric flask, and placing the volumetric flask on a shaking table for shaking or ultrasonic treatment to completely disintegrate the pellets in the sustained release capsule. Adding water with volume of 20% of that of the volumetric flask, performing ultrasound for 15 minutes, cooling, fixing volume to scale with water, and mixing uniformly. Transferring part of the sample solution filtering membrane, and taking and analyzing the subsequent filtrate sample.
HPLC chromatographic conditions for sample detection were as follows: mobile phase a: buffer salt at ph 6.2: methanol=48: 52 (V/V); mobile phase B: buffer salt at ph 6.2: acetonitrile=48: 52 (V/V); octadecylsilane chemically bonded silica is used as a filler for the chromatographic column; the detection wavelength is UV 239nm; the column temperature is 45 ℃; the sample injection volume is 10 mu L; the flow rate was 1.2 ml/min and the mobile phase was subjected to a linear gradient elution as follows:
Figure BDA0004021241580000081
Figure BDA0004021241580000091
2. test results
The total amount of impurities measured at various time points for the sustained-release capsules of examples 1 to 3 and comparative example 3 are shown in Table 2 below.
TABLE 2 total impurity levels (%)'s for inventive examples 1-3 and comparative example 3 at different time points
Sampling time Example 1 Example 2 Example 3 Comparative example 3
For 0 month <0.05 <0.05 <0.05 0.2
1 month <0.05 <0.05 <0.05 1.0
2 months of <0.05 <0.05 <0.05 —
For 3 months <0.05 <0.05 <0.05 —
Note that: "-" indicates that the total amount of impurities at the previous sampling point is too high to continue the measurement of the total amount of impurities at that sampling point.
As can be seen from a combination of tables 1 and 2, in-vitro dissolution behavior of comparative example 3 (high-content ethylcellulose formulation) using ethanol as a coating solvent is similar to that of the reference formulation, but the impurity content after 2 months is greater than 1.0%, which proves that the sustained-release capsule using ethanol as a coating solvent can solve the problem of in-vitro release degree by increasing the content of ethylcellulose, but still causes the problem of storage stability, so that ethanol is not suitable as a coating solvent for cyclobenzaprine hydrochloride sustained-release capsules.
In contrast, examples 1-3 using isopropyl alcohol as a coating solvent still have a total impurity content of less than 0.05% after being placed at 40 ℃ and 75% RH for 3 months, which proves that the cyclobenzaprine hydrochloride sustained-release capsule prepared by using isopropyl alcohol as a coating solvent has an excellent chemical stabilizing effect.
Although specific embodiments of the invention have been described, those skilled in the art will recognize that many changes and modifications may be made thereto without departing from the scope or spirit of the invention. Accordingly, the present invention is intended to embrace all such alterations and modifications that fall within the scope of the appended claims and equivalents thereof.

Claims (10)

1. The cyclobenzaprine hydrochloride sustained-release capsule is characterized in that the content of the sustained-release capsule comprises sustained-release coated pellets, the sustained-release coated pellets are prepared from blank pellet cores and a drug-containing sustained-release coating layer, the drug-containing sustained-release coating layer comprises a cyclobenzaprine hydrochloride Lin Hehuan release material, and a coating solvent used in the coating process of the sustained-release coated pellets does not contain ethanol or water.
2. The cyclobenzaprine hydrochloride sustained-release capsule of claim 1, wherein the coating solvent is selected from one or more of isopropanol, n-propanol, n-butanol, and tert-butanol.
3. The cyclobenzaprine hydrochloride sustained release capsule of claim 2, wherein the coating solvent is isopropanol.
4. The cyclobenzaprine hydrochloride sustained-release capsule according to claim 1, wherein the sustained-release material is selected from one or more of ethylcellulose and acrylic resin.
5. The cyclobenzaprine hydrochloride sustained release capsule of claim 1, wherein the blank pellet core is a sucrose pellet core.
6. The cyclobenzaprine hydrochloride sustained release capsule of claim 1, wherein the contents of the sustained release capsule further comprise a lubricant.
7. The cyclobenzaprine hydrochloride sustained release capsule of claim 1, wherein the sustained release coating layer further comprises a plasticizer.
8. The method for preparing cyclobenzaprine hydrochloride sustained-release capsules according to any one of claims 1 to 7, comprising the following steps:
(1) Dissolving the cyclobenzaprine hydrochloride, the slow release material and the optional plasticizer with the prescription amount in a coating solvent to prepare coating liquid;
(2) Slowly spraying the coating liquid prepared in the step (1) on blank pellet cores in a fluidized bed coating machine to prepare slow-release coated pellets;
(3) Mixing the slow-release coated micropellets with optional lubricant, and encapsulating to obtain the final product;
the coating solvent used in step (1) does not contain ethanol or water.
9. Use of a cyclobenzaprine hydrochloride sustained release capsule according to any one of claims 1-7 in a medicament for alleviating local muscle spasms and their concomitant symptoms.
10. Use of a coating solvent for improving the in vitro release and/or chemical stability of cyclobenzaprine hydrochloride sustained release capsules according to any of claims 1 to 7, characterized in that said coating solvent does not contain ethanol or water.
CN202211691406.XA 2022-12-27 2022-12-27 Cyclobenzaprine hydrochloride sustained-release capsule and preparation method thereof Pending CN116172976A (en)

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