CN200998435Y - Tizanidine and the novel agent of the derivant thereof - Google Patents
Tizanidine and the novel agent of the derivant thereof Download PDFInfo
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- CN200998435Y CN200998435Y CNU2006200363966U CN200620036396U CN200998435Y CN 200998435 Y CN200998435 Y CN 200998435Y CN U2006200363966 U CNU2006200363966 U CN U2006200363966U CN 200620036396 U CN200620036396 U CN 200620036396U CN 200998435 Y CN200998435 Y CN 200998435Y
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- tizanidine
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- 229960000488 tizanidine Drugs 0.000 title claims abstract description 67
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- 241001597008 Nomeidae Species 0.000 title claims description 14
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Images
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The utility model relates to a new dosage form of tizanidine and the derivatives of the tizanidine, which consists of at least one tablet core and at least a wrapping layer. The tablet core and the wrapping layer are respectively the ordinary release parts (1) or sustained release parts (2) of the Tizanidine. According to the medicine effect tests, the treatment effect of the new preparation is considerably higher than the sustained release preparation, and the untoward reaction rate of the new dosage form is considerably less than the untoward reaction rate of the ordinary release preparation, and thus the utility model provides a highly efficient and safe new dosage form for the clinical application of the tizanidine and the derivatives of the tizanidine.
Description
Technical field
This utility model relates to the novel form of a kind of tizanidine and derivant thereof.
Background technology
The structural formula of tizanidine and derivant thereof suc as formula 1 and formula 2 shown in:
Its Chinese style 1 is tizanidine's structural formula, and formula 2 is tizanidine's derivant structure formula.
Wherein R is available organic acid or mineral acids such as hydrochloric acid, nitric acid, sulphuric acid, fumaric acid, citric acid, methanesulfonic acid, p-methyl benzenesulfonic acid.
Tizanidine hydrochloride, chemistry 5-chloro-4-(2-imidazoline-2-amino)-2,1,3 Bian sulthiam hydrochlorates by name.Be the central skeletal muscle relaxant, be used to reduce because of skeleton muscular hypertonia, muscular spasm and myotonia due to brain and trauma of spinal cord, cerebral hemorrhage, encephalitis and the multiple sclerosis disease etc.Domestic its conventional tablet of existing manufacturer production, specification is 4mg.The tizanidine hydrochloride structural formula is as shown in Equation 3:
At multiple dose, in the clinical research of placebo, 264 patients give the tizanidine, and 261 give placebo, and the generation of untoward reaction that comprises several serious adverse events in the drug treating group is than placebo class frequency height.In the multiple dose placebo-controlled study, because the generation of untoward reaction and the patient of Halfway Stopping administration has 45 (17%) in 264 patients that accept tizanidine's treatment, giving has 13 (5%) among 261 patients of placebo.After withdrawing from treatment, they usually narrate the reason of 2 or above withdrawal.Cause the adverse events of the most normal appearance of drug withdrawal to have: tired (3%), drowsiness (3%), xerostomia (3%), spasm extent or tension force increase (2%) or dizzy (2%).
Single dose gives in the research that 142 experimenters of placebo participate in, except above-mentioned common adverse events, also has hypotension and bradycardia (incidence rate＞2%).The clinical research of a single-dose shows, 2/3 patient's systolic pressure or diastolic pressure descend 20% in 8mg tizanidine's processed group, hypotension 1h after administration occurs, 2-3h reaches the peak, sometimes accompany bradycardia, the orthostatism hypotension, slight headache, giddy, the few appearance faints, this hypotension is imitated and is dose dependent, during greater than 2mg, begin to monitor blood pressure at single dose. by adjusting dosage and keep a close eye on hypotensive sings and symptoms before adjusting dosage, significantly hypotension may be able to descend greatly.In addition, when patient when clinostatism transfers erect position to, the risk of hypotension and postural hypotension is just bigger.
The first use of patient should have the dose titration phase in 2～4 weeks.Each 2～the 4mg of beginning consumption, 6～8 hours 1 time.Single agent consumption generally is no more than 8mg, and a consumption per day generally is no more than 24mg.Maximum consumption is 36mg every day.Because of this product is oral stronger first pass effect is arranged, will note individuation of dosage during use.Need according to the character of medicine, clinical consumption and specifically at the indication analysis-by-synthesis, amount of drug when determining concrete dosage form and preparation.Because this drug administration cycle is long, general formulation can not satisfy clinical demand.
Still have nothing to do at present in the report of the multiple structure preparation of tizanidine and derivant thereof.
The utility model content
The purpose of this utility model provides the novel form of a kind of tizanidine and derivant thereof, is used to overcome took especially hypotension phenomenon of untoward reaction that tizanidine's preparation produces in the past.
This utility model novel form be by at least one sheet heart and at least one deck integument constitute, the sheet heart and integument are respectively tizanidine's often release part (1) or slow-released part (2).
The described slow-released part (2) that the heart is the tizanidine, integument are tizanidine's often release part (1) or slow-released part (2).
Further, often release part (1) or slow-released part (2) alternately wrap up.Can also comprise coatings (3).Wherein, coatings also can be used as integument.
The slow-released part of this utility model novel form (2) adjuvant comprises: one, the less high molecular polymer of water insoluble or water solublity.Common have ethyl cellulose, polyethylene, polypropylene, poly-silica ball, ethylene-vinyl acetate copolymer and a polymethyl methacrylate etc.Hydrophilic gel class material.Be meant and meet water and Digestive system expands, form the gel barrier and control the hydrophilic polymer of medicine stripping.Two, bioerodable section bar material.Commonly used have stearic acid, Brazil wax, glyceryl monostearate, a stearyl alcohol etc.Three, hydrophilic gel class material.Mainly contain natural gum class such as the acid of Sargassum sodium, agar, tragcanth; Cellulose derivative such as methylcellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose etc.
Wherein adopt the different ratio of adjuvant of above-mentioned slow-released part, can be prepared into the slow-release auxiliary material of different size and different drug release times.
Wherein coatings is a conventional tablet coating adjuvant.
Also but the applying solid dispersion technology prepares slow-released part, and the solid dispersion carrier material has non-stimulated, nontoxic, not with medicine generation chemical reaction, does not influence the curative effect and the stability of principal agent, can make medicine reach the optimum dispersion state, and advantage cheap and easy to get.Carrier material commonly used has water solublity, slightly solubility and enteric solubility carrier material three major types.Water-solubility carrier material commonly used has high molecular polymer (as polyethylene glycols, polyvinylpyrrolidone etc.), surfactant, organic acid and saccharide (as sorbitol, sucrose) etc.; The slightly solubility carrier material has cellulose (as ethyl cellulose), acrylic resin etc.; The enteric solubility carrier material has cellulose family (as cellulose acetate phthalate ester etc.), polyacrylic resin (as II number, III acrylic resin).Because SM-3997 is slightly water-soluble, absorption than other insoluble or enteric solubility carrier make the dispersion good absorbing of human body to the solid dispersion made with water-solubility carriers such as PEG found in experiment, so this utility model solid dispersion is selected water-solubility carriers such as PEG, PVP for use.
Prove that according to the test of pesticide effectiveness therapeutic effect of this utility model novel formulation is apparently higher than slow releasing preparation, adverse reaction rate is starkly lower than normal release formulation, and the novel form of a kind of not only efficient but also safety is provided for clinical practice tizanidine and derivant thereof.
Description of drawings
Fig. 1 this utility model multilayer tablet profile (embodiment 1)
Fig. 2 this utility model multilayer tablet profile (embodiment 2)
Fig. 3 this utility model multilayer tablet profile (embodiment 8)
Fig. 4 this utility model multilayer tablet profile (embodiment 9)
Fig. 5 this utility model multilayer tablet profile (embodiment 10)
Fig. 6 this utility model multilayer tablet profile (embodiment 11)
The specific embodiment
The preparation of embodiment 1 this utility model novel form (tizanidine's mol ratio is 70: 30 in often release part and the slow-released part) (see figure 1)
Raw material: tizanidine hydrochloride 2g, hydroxypropyl emthylcellulose (HPMC K4M) 64.8g, lactose 110g, starch 100g, microcrystalline Cellulose 5g, 75% ethanol an amount of (1000), method for making is as follows:
A, get tizanidine hydrochloride 0.6g, add hydroxypropyl emthylcellulose (HPMC K4M) and lactose, be prepared into slow-released part (slow-released part (2)) internal layer label;
B, get tizanidine hydrochloride 1.4g and add microcrystalline Cellulose and make often release part (often release part (1)), be coated on step a gained label skin, coating;
C, get step b gained coating, add starch and be prepared from.
The preparation of embodiment 2 this utility model novel forms (tizanidine's mol ratio is 65: 35 in often release part and the slow-released part) (see figure 2)
Raw material: tizanidine hydrochloride 4g, tragcanth 20g, correctives 1.5g, distilled water an amount of, starch 80g, dextrin 20g (1000), method for making is as follows:
A, get tizanidine hydrochloride 1.4g, add tragcanth, be prepared into slow-released part (slow-released part (2)) internal layer label;
B, get tizanidine hydrochloride 2.6g and add dextrin and make often release part (often release part (1)), be coated on step a gained label skin, coating;
C, get step b gained coating, add starch, correctives is prepared from.
The preparation of embodiment 3 this utility model novel forms (tizanidine's mol ratio is 75: 25 in often release part and the slow-released part)
Raw material: tizanidine hydrochloride 4g hydroxypropyl emthylcellulose (HPMC K100M) 50g, methylcellulose 45g, starch 80g, microcrystalline Cellulose 20g (1000), method for making is as follows:
A, get tizanidine hydrochloride 1.0g, add hydroxypropyl emthylcellulose (HPMC K100M), methylcellulose and starch, be prepared into slow-released part (slow-released part (2)) internal layer label;
B, get tizanidine 3.0g and add microcrystalline Cellulose and make often release part (often release part (1)), be coated on step a gained label skin, coating;
C, get step b gained coating, add starch and be prepared from.
The preparation of embodiment 4 this utility model novel forms (tizanidine's mol ratio is 66: 34 in slow-released part and the often release part)
Raw material: tizanidine hydrochloride 2g, sodium alginate 25g, methylcellulose 50g, carboxymethyl cellulose 25g, 75% alcoholic solution 10ml, corn starch 100g (1000), method for making is as follows:
A, get tizanidine hydrochloride 0.68g, add sodium alginate, methylcellulose and carboxymethyl cellulose, be prepared into slow-released part (slow-released part (2)) internal layer label;
B, get tizanidine hydrochloride 1.32g and add corn starch and make often release part (often release part (1)), be coated on step a gained label skin, coating;
C, get step b gained coating, add corn starch and be prepared from.
The preparation of embodiment 5 this utility model novel forms (tizanidine's mol ratio is 70: 30 in slow-released part and the often release part)
Raw material: sulphuric acid tizanidine 8g, tragcanth 5g, 75% alcoholic solution are an amount of, corn starch 70g, lactose 60g, distilled water 1000ml, starch 80g, dextrin 20g (1000), and method for making is as follows:
A, get sulphuric acid tizanidine 2.4g, add tragcanth, lactose, be prepared into slow-released part (slow-released part (2)) internal layer label;
B, get sulphuric acid tizanidine 5.6g and add corn starch and make often release part (often release part (1)), be coated on step a gained label skin, coating;
C, get step b gained coating, add starch and dextrin and be prepared from.
The preparation of embodiment 6 this utility model novel forms
Raw material: citric acid tizanidine 5g, hydroxypropyl emthylcellulose (HPMC K100M) 50g methylcellulose 45g, 75% ethanol are an amount of, Icing Sugar 400g, dextrin 200g, soluble starch 400g (1000 capsules), and method for making is as follows:
A, get citric acid tizanidine 1.5g, add hydroxypropyl emthylcellulose (HPMC K100M), methylcellulose, be prepared into slow-released part (slow-released part (2)) inner layer granule;
B, get citric acid tizanidine 3.5g and add corn starch and make often release part (often release part (1)), be coated on step a gained granule skin, coating;
C, get step b gained coating, add Icing Sugar, starch and dextrin and be prepared into wet granular, drying, granulate, encapsulated.
In addition, the granule direct compression of described preparation can be prepared into tablet.
The preparation of embodiment 7 this utility model medicines
Raw material: fumaric acid tizanidine 2g, hydroxypropyl emthylcellulose (HPMC K4M) 64.8g, an amount of, the lactose 1100g (1000 bags of granules) of 75% ethanol.
A, get fumaric acid tizanidine 0.6g, add hydroxypropyl emthylcellulose (HPMC K4M), be prepared into slow-released part (slow-released part (2)) inner layer granule;
B, get fumaric acid tizanidine 1.4g and add lactose and make often release part (often release part (1)), be coated on step a gained granule skin, coating;
C, get step b gained coating, add lactose and be prepared into wet granular, drying.
In addition, the granule direct compression of described preparation can be prepared into tablet.
The preparation of embodiment 8 this utility model novel forms (tizanidine's mol ratio is 70: 30 in often release part and the slow-released part) (see figure 3)
Raw material: tizanidine hydrochloride 2g, hydroxypropyl emthylcellulose (HPMC K4M) 34.8g, lactose 110g, starch 100g, polyethylene 20g, microcrystalline Cellulose 5g, 75% ethanol an amount of (1000).
Method for making is as follows:
A, get tizanidine hydrochloride 0.3g, add hydroxypropyl emthylcellulose (HPMC K4M) and lactose, be prepared into slow-released part (slow-released part (2)) internal layer label;
B, get tizanidine hydrochloride 0.3g, add polyethylene and lactose, be prepared into slow-released part (slow-released part (2));
C, the slow-released part that a, b step are prepared mix, and get label; Get tizanidine hydrochloride 1.4g adding microcrystalline Cellulose and make the often release part, coat gained label skin, coating (often release part (1)); Tabletting is prepared into tablet.
The preparation of embodiment 9 this utility model novel forms (tizanidine's mol ratio is 70: 30 in often release part and the slow-released part)
Raw material: tizanidine hydrochloride 2g, hydroxypropyl emthylcellulose (HPMC K4M) 24.5g, hydroxyethyl-cellulose 31.1g, lactose 90g, starch 110g, microcrystalline Cellulose 5g, 75% ethanol an amount of (1000).
Method for making is as follows:
A, get tizanidine hydrochloride 0.1g, add hydroxypropyl emthylcellulose (HPMC K4M) and lactose, be prepared into slow-released part (slow-released part (2)) internal layer label;
B, get tizanidine hydrochloride 1.0g and add microcrystalline Cellulose and make often release part (often release part (1)), be coated on step a gained label skin, coating;
C, get tizanidine hydrochloride 0.5g and add hydroxyethyl-cellulose and make slow-released part (slow-released part (2)), be coated on step b gained label skin, coating;
D, get tizanidine hydrochloride 0.4g and add microcrystalline Cellulose and make often release part (often release part (1)), be coated on step c gained label skin, coating;
E, get step b gained coating, add starch and be prepared from.
This utility model slow-released part (2) is meant the slow-released part of the arbitrary supplementary product compatibility preparation among the embodiment 1～9, but the adjuvant that is not limited only among the embodiment to be adopted.
The preparation of embodiment 10 this utility model novel forms
The often release part (1) of getting embodiment 1 preparation directly is pressed into plain sheet, and the slow-released part (2) that embodiment 2 is prepared directly is pressed into plain sheet, merges two plain sheets, compacting, and coating is prepared into the multilayer tablet (see figure 5).
The preparation of embodiment 11 this utility model novel forms
Get often release part (1), slow-released part (2) the branch laminate of embodiment 1 preparation, be prepared into multilayer tablet.See that Fig. 6 is following by concrete pharmacodynamics test proof the beneficial effects of the utility model.
Test example 1: the screening test of often release part and slow release slow release proportioning in this utility model tizanidine novel form
Trial drug: tizanidine's mol ratio is respectively 65: 35,70: 30,75: 25 methods by embodiment 1 and is prepared into double-deck tablet in often release part and the slow-released part.
Experimental technique:
Patient: introduce patient by 20 general practitioners and study.Patient adds up to 120 people, is divided into 6 groups at random.There was the acute lumbago and backache of moderate degree at least at age from 18～70 years old, and outbreak is arranged recently, followed or do not accompany the marrow sciatica, also had lumbar vertebra pain to cause the patient of limitation of movement to participate in research this time simultaneously.Anemia of pregnant woman's (doing inspection), women breast-feeding their children, malignant tumor patient, sclerotin dredge the patient, before lumbar surgery history or need the patient of surgical procedure all to be left out were arranged.Those have tangible systemic disease and those other rheumatismal medical history or patients except that osteoarthritis also to foreclose simultaneously.
Patient is under an embargo and uses other tranquilizer, anti-inflammatory agent, spasmolytic, muscle relaxant (comprising ethanol) or antianxiety drugs, depressor or anticoagulant during studying.
Design: this be according to Declaration of Helsinki (Venice, 1983) carry out at random, the research of double blinding, placebo parallel control.Give in placebo, often release part and the slow-released part in tizanidine's mol ratio (65: 35), often release part and the slow-released part tizanidine's mol ratio (75: 25) in tizanidine's mol ratio (70: 30), often release part and the slow-released part respectively, (specification is 4mg to tizanidine's conventional formulation, 3 times/day) and tizanidine's slow-released part (12mg, 1 time/day).Report Ethics Committee to agree, the signature Informed Consent Form.Give 7 days Drug therapy, estimate then.
Estimate: patient will carry out medical inspection when entering research, the recording medicine history, and the suitable degree that patient enters research also is examined.The results are shown in Table 1.
Table 1 patient daily record is to the evaluation of pain: average visual simulation scoring
| Trial drug | Effective percentage (%) | Adverse reaction rate (%) |
| In placebo Tizanidine conventional formulation group often release part and the slow-released part in Tizanidine mol ratio (65: 35) group often release part and the slow-released part in Tizanidine mol ratio (70: 30) group often release part and the slow-released part Tizanidine mol ratio (75: 25) organize Tizanidine sustained release preparation group | 31 82 87 86 85 65 | 21 41 30 23 31 29 |
Annotate: conventional formulation is general normal release formulation such as tablet, capsule or granule.Untoward reaction shows as tired, headache, dizzy, dizziness and xerostomia in this experiment.
Tizanidine's mol ratio (70: 30) group, often release part are compared with tizanidine's mol ratio (75: 25) group in the slow-released part in tizanidine's mol ratio (65: 35) group in tizanidine's conventional formulation group, often release part and the slow-released part, often release part and the slow-released part, and its effective percentage does not have marked difference (P＞0.05).Tizanidine's mol ratio (70: 30) group compares with tizanidine's conventional formulation group that there were significant differences in adverse reaction rate often release part and the slow-released part, so the ratio of this utility model preferred tizanidine often release part and slow-released part is 70: 30.
The novel form of this utility model tizanidine and derivant thereof, be used for local pain diseases such as neck, shoulder and flank pain, cerebrovascular accident, operation sequela (spinal cord injury, cerebral lesion), spinocerebellar degeneration, multiple sclerosis, diseases such as amyotrophic lateral sclerosis can effectively overcome and take especially hypotension phenomenon of untoward reaction that tizanidine's preparation produces in the past; The novel form of a kind of not only efficient but also safety is provided for clinical practice tizanidine and derivant thereof.
Claims (4)
1, the novel form of a kind of tizanidine and derivant thereof is characterized in that: it be by at least one sheet heart and at least one deck integument constitute, the sheet heart and integument are respectively tizanidine's often release part (1) or slow-released part (2).
2, the novel form of tizanidine according to claim 1 and derivant thereof is characterized in that: the described heart is tizanidine's slow-released part (2), and integument is tizanidine's often release part (1) or a slow-released part (2).
3, the novel form of tizanidine according to claim 1 and derivant thereof is characterized in that: often release part (1) or slow-released part (2) be parcel alternately.
4, the novel form of tizanidine according to claim 1 and derivant thereof is characterized in that: also comprise coatings (3).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNU2006200363966U CN200998435Y (en) | 2006-11-24 | 2006-11-24 | Tizanidine and the novel agent of the derivant thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNU2006200363966U CN200998435Y (en) | 2006-11-24 | 2006-11-24 | Tizanidine and the novel agent of the derivant thereof |
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| Publication Number | Publication Date |
|---|---|
| CN200998435Y true CN200998435Y (en) | 2008-01-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNU2006200363966U Expired - Lifetime CN200998435Y (en) | 2006-11-24 | 2006-11-24 | Tizanidine and the novel agent of the derivant thereof |
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| Country | Link |
|---|---|
| CN (1) | CN200998435Y (en) |
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2006
- 2006-11-24 CN CNU2006200363966U patent/CN200998435Y/en not_active Expired - Lifetime
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Address after: 646000 national high tech Zone, Sichuan, Luzhou Province Pharmaceutical Industrial Park Patentee after: Sichuan Keruide pharmaceutical Limited by Share Ltd Address before: 646106 Luzhou city of Sichuan province Luxian County Fu Town Industrial Park Sichuan Keruide Pharmaceutical Co Ltd Patentee before: Keruide Pharmaceutical Co., Ltd., Sichuan |
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