CN109316457B - Cyclobenzaprine hydrochloride sustained release preparation and preparation method thereof - Google Patents
Cyclobenzaprine hydrochloride sustained release preparation and preparation method thereof Download PDFInfo
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- CN109316457B CN109316457B CN201811412749.1A CN201811412749A CN109316457B CN 109316457 B CN109316457 B CN 109316457B CN 201811412749 A CN201811412749 A CN 201811412749A CN 109316457 B CN109316457 B CN 109316457B
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- tablet
- cyclobenzaprine hydrochloride
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- diclofenac sodium
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- VXEAYBOGHINOKW-UHFFFAOYSA-N cyclobenzaprine hydrochloride Chemical compound Cl.C1=CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 VXEAYBOGHINOKW-UHFFFAOYSA-N 0.000 title claims abstract description 43
- 229960000500 cyclobenzaprine hydrochloride Drugs 0.000 title claims abstract description 39
- 239000003405 delayed action preparation Substances 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 229960001193 diclofenac sodium Drugs 0.000 claims abstract description 22
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 claims abstract description 22
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 8
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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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the field of pharmaceutical preparations, in particular to a cyclobenzaprine hydrochloride sustained-release preparation and a preparation method thereof. The cyclobenzaprine hydrochloride sustained release preparation is a core-coated tablet, the inner core tablet comprises active ingredients of cyclobenzaprine hydrochloride and diclofenac sodium, a sustained release agent, a diluent, a binding agent, a disintegrating agent and a lubricant, the middle layer is a sustained release coating layer, and the outer layer has the same composition as the inner core tablet. The core-spun tablet disclosed by the invention selects cross-linked sodium alginate and chitosan as slow-release agents, selects cyclobenzaprine hydrochloride and diclofenac sodium as active ingredients, and tests show that the core-spun tablet prepared by combining the cyclobenzaprine hydrochloride and the diclofenac sodium achieves a synergistic effect compared with the core-spun tablet prepared by only adopting one analgesic active ingredient, namely cyclobenzaprine hydrochloride or diclofenac sodium.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a cyclobenzaprine hydrochloride sustained-release preparation and a preparation method thereof.
Background
Cyclobenzaprine hydrochloride (1) with the chemical name of 5- (3-dimethylaminopropylene) dibenzo [ a, d ] cycloheptene hydrochloride is a muscle relaxant developed by Merck in the United states, is marketed in many countries and has the trade name of Flexiril.
Cyclobenzaprine hydrochloride is a central muscle relaxant, the action part of the cyclobenzaprine hydrochloride is probably in the brainstem and is not a ganglionic muscle blocker, skeletal muscle relaxant effect appears after administration, and the cyclobenzaprine hydrochloride also has choline resistance effect, can relieve local muscle spasm symptoms, does not interfere normal functions of muscles, and has no effect on muscle plague contracture caused by central nervous system diseases. The composition is mainly used for treating the painful local muscle spasm in clinic.
Cyclobenzaprine hydrochloride is able to alleviate or eliminate the hypersensitive state of muscles in a variety of animal models. Animal studies suggest that cyclobenzaprine hydrochloride does not directly interfere with animal muscle nerve function or directly affect skeletal muscle function, and that it acts primarily on the brain portion of the central nervous system, rather than directly controlling muscle spasm and relaxing the bony muscularis. Evidence suggests that cyclobenzaprine hydrochloride achieves a muscle relaxation effect by affecting motor nerve fibers and reducing abnormal muscle movements.
Diclofenac sodium (1) belongs to the third-generation potent non-steroidal anti-inflammatory drugs, mainly inhibits the metabolism of arachidonic acid by inhibiting cyclooxygenase so as to reduce the synthesis of prostaglandin and the generation of platelets, and inhibits lipoxygenase to a certain extent so as to reduce the generation of products such as leukotriene, bradykinin, and particularly has more obvious inhibition effect on leukotriene beta 4, and has the effects of relieving fever, easing pain and diminishing inflammation by inhibiting inflammatory factors. The mechanism of diclofenac sodium for treating neuropathic pain is that the production of prostasin is reduced by inhibiting the activity of epoxidase highly expressed in damaged nerve and spinal cord, so that the expression of P Substance (SP) and calcitonin gene related peptide (CG RP) in dorsal root ganglion and spinal cord dorsal horn superficial layer is correspondingly reduced, and the analgesic effect is further exerted.
Diclofenac sodium is an aryl acetic acid non-steroidal anti-inflammatory drug, is widely applied to various chronic osteoarticular pains, has 2-2.5 times stronger analgesic, anti-inflammatory and antipyretic effects than indomethacin and 26-50 times stronger than aspirin compared with similar drugs, and is a novel powerful anti-inflammatory analgesic.
However, cyclobenzaprine hydrochloride and diclofenac sodium have the problems of quick oral absorption and short biological half-life, and common dosage forms of the cyclobenzaprine hydrochloride and the diclofenac sodium need to be taken for many times every day, so that the administration compliance of patients is influenced. At present, no research and report on the combination preparation of sustained-release preparations by the ciclopirox hydrochloride and the diclofenac sodium exist.
Disclosure of Invention
The invention aims to provide a cyclobenzaprine hydrochloride sustained-release preparation with excellent analgesic effect and a preparation method thereof.
The technical scheme for solving the technical problem is that the cyclobenzaprine hydrochloride sustained-release preparation is a core-spun tablet, an inner core tablet comprises active ingredients of cyclobenzaprine hydrochloride and diclofenac sodium, a sustained-release agent, a diluent, a binder, a disintegrant and a lubricant, an intermediate layer is a sustained-release coating layer, and the composition of an outer layer is the same as that of the inner core tablet.
The weight part ratio of the cyclobenzaprine hydrochloride to the diclofenac sodium in the core-spun tablets and the outer layer is 1-5: 1-10.
The weight ratio of the inner chip to the outer layer is 3-9: 2-6, and preferably 3: 2.
The dosage of the slow-release coating layer is 1-5%.
The slow release agent is composed of cross-linked sodium alginate and chitosan, and the ratio of the cross-linked sodium alginate to the chitosan is 1-10: 1-10.
The diluent comprises one or more of microcrystalline cellulose, compressible starch, dextrin, mannitol, and sorbitol.
The adhesive comprises one or more of starch slurry, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose.
The disintegrating agent comprises one or more of dry starch, croscarmellose sodium, alginic acid and low-substituted hydroxypropyl cellulose.
The lubricant comprises one or more of talcum powder, magnesium stearate and aerosil.
The cyclobenzaprine hydrochloride sustained release preparation comprises the following components in parts by weight: 1-6 parts of cyclobenzaprine hydrochloride, 1-4 parts of diclofenac sodium, 15-30 parts of a diluent, 2-10 parts of an adhesive, 10-20 parts of a disintegrating agent and 0.1-1 part of a lubricating agent.
The invention also provides a preparation method of the cyclobenzaprine hydrochloride sustained release preparation, which comprises the following steps:
(1) weighing the raw materials according to the formula proportion;
(2) pressing the inner core tablet, coating, and pressing the core tablet.
The invention has the beneficial effects that:
the core-spun tablet disclosed by the invention selects cross-linked sodium alginate and chitosan as slow-release agents, selects cyclobenzaprine hydrochloride and diclofenac sodium as active ingredients, and tests show that the core-spun tablet prepared by combining cyclobenzaprine hydrochloride and diclofenac sodium achieves a synergistic effect compared with the core-spun tablet prepared by only adopting cyclobenzaprine hydrochloride or diclofenac sodium as analgesic active ingredients.
Drawings
FIG. 1 is a graph showing the time effect test of the analgesic effect of cyclobenzaprine hydrochloride core-spun tablets
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are exemplary only.
EXAMPLE preparation of cyclobenzaprine hydrochloride core tablets
The cyclobenzaprine hydrochloride core-coated tablet is prepared according to the formula (g/tablet) in the table 1, the inner core tablet is firstly pressed, then coated, and finally the core-coated tablet is pressed, thus obtaining the cyclobenzaprine hydrochloride core-coated tablet.
TABLE 1 formula of cyclobenzaprine hydrochloride core-wrapped tablets
Experimental example time effect test of analgesic effect of cyclobenzaprine hydrochloride core-wrapped tablet by mouse hot plate method
And (3) placing the female mouse of Kunming species on a hot plate pain measuring instrument at the temperature of (55 +/-1) DEG C, immediately timing, stopping timing when the first time licking or stamping of the foot occurs, and taking the obtained time as a basic pain threshold. Selecting 60 mice with a basal pain threshold of more than 5 seconds and less than 30 seconds, randomly dividing the mice into 6 groups, using cyclobenzaprine hydrochloride sustained-release preparations of examples 1-3 and a comparative ratio of 1-3 to administer the mice in an administration amount of 0.2 mg.kg-1, measuring the pain threshold at 1, 2, 4, 8, 12, 20 and 24 hours after administration, calculating the maximum possible pain easing percentage by self comparison before and after administration (PMAP), and taking the absence of licking or postlicking of 60s as the percentage of analgesia, wherein the calculation formula is as follows:
the results are shown in FIG. 1.
As can be seen from FIG. 1, the tablets of comparative examples 1 to 3 have analgesic effects similar to those of the conventional double-layer tablets, with no sustained release agent added to the inner core tablet and the outer layer, and a peak appears around 8 hours, and analgesic effects disappear gradually after 12 hours, while examples 1 to 3 of the present application have sustained release effects due to the addition of crosslinked sodium alginate and chitosan as sustained release agents to the inner core tablet and the outer layer, and the core-coated tablets of examples 1 to 3 have ideal analgesic effects around 4 hours and can last for 24 hours.
Moreover, as can be seen from the comparison between examples 1 to 3, examples 2 to 3 all use only one analgesic active ingredient cyclobenzaprine hydrochloride or diclofenac sodium, and the PMAP maximum of the cyclobenzaprine hydrochloride or diclofenac sodium is about 50%, while example 1 uses cyclobenzaprine hydrochloride and diclofenac sodium in combination, and the PMAP maximum of the cyclobenzaprine hydrochloride and diclofenac sodium is more than 80%, so that a synergistic effect is generated.
The foregoing detailed description of the invention has been presented for purposes of illustration and description, and is intended to be by way of illustration only and is not intended to limit the scope of the invention, its application, or uses, including the best mode, of manufacture, of the invention. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention. The scope of patented protection of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.
Claims (1)
1. The cyclobenzaprine hydrochloride sustained release preparation is characterized by being a core-coated tablet, wherein the composition of an inner chip is 0.0045 g/tablet of cyclobenzaprine hydrochloride, 0.0045 g/tablet of diclofenac sodium, 0.02 g/tablet of microcrystalline cellulose, 0.02 g/tablet of methyl cellulose, 0.015 g/tablet of cross-linked sodium alginate, 0.015 g/tablet of chitosan, 0.025 g/tablet of low-substituted hydroxypropyl cellulose, 0.015 g/tablet of cross-linked sodium carboxymethyl cellulose and 0.001 g/tablet of talcum powder, an intermediate layer is 0.015 g/tablet of 5% cross-linked sodium alginate solution and 0.015 g/tablet of 5% chitosan, an outer layer is 0.003 g/tablet of cyclobenzaprine hydrochloride, 0.003 g/tablet of diclofenac sodium, 0.01 g/tablet of chitosan, 0.015 g/tablet of microcrystalline cellulose, 0.015 g/tablet of methyl cellulose, 0.01 g/tablet of crosslinked sodium alginate, 0.02 g/tablet of low-substituted hydroxypropyl cellulose, 0.01 g/tablet of crosslinked sodium carboxymethylcellulose and 0.001 g/tablet of talcum powder.
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| CN1452983A (en) * | 2003-05-20 | 2003-11-05 | 广州贝氏药业有限公司 | Delayed-releasing compound diclofenac sodium prepn |
| CA2573705A1 (en) * | 2004-07-29 | 2006-02-02 | Sanofi-Aventis | Pharmaceutical multilayer tablet for controlled release of active ingredients with highly ph-dependent solubility |
| BRPI0602179A (en) * | 2006-06-08 | 2008-01-22 | Biolab Sanus Farmaceutica Ltda | pharmaceutical composition comprising cyclobenzaprine and aceclofenac in combination |
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| CN103655505B (en) * | 2013-12-23 | 2016-10-26 | 闻晓光 | A kind of pain relieving class two-layer release-controlled tablet and preparation method thereof |
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