CN1961859B - Novel formulation of Tizanidine and derivative thereof and preparation method thereof - Google Patents
Novel formulation of Tizanidine and derivative thereof and preparation method thereof Download PDFInfo
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- CN1961859B CN1961859B CN2006100223240A CN200610022324A CN1961859B CN 1961859 B CN1961859 B CN 1961859B CN 2006100223240 A CN2006100223240 A CN 2006100223240A CN 200610022324 A CN200610022324 A CN 200610022324A CN 1961859 B CN1961859 B CN 1961859B
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- tizanidine
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Abstract
The invention relates to a nizatidine and it's derivate, wherein it contains the general-release paret whose active compotents are nizatidine and its derivate, and the slow-release part, while the mol ratio between nizatidine and derivate are 5-95:5-95. The invention also provides a relative preparation. The test has proves that its effect is higher than slow-release agent, and its rate of side effect is lower than general-release agent.
Description
Technical field
The present invention relates to the novel form of tizanidine and derivant thereof, belong to drug world.
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.
Formula 1
Formula 2
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:
Formula 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, begins 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.
Summary of the invention
Technical problem to be solved by this invention provides the novel form of a kind of tizanidine and derivant thereof, is used to overcome took the hypotension phenomenon that tizanidine's preparation produces in the past.The present invention also provides the preparation method of this novel form.
The invention provides the novel form of a kind of tizanidine and derivant thereof, be mainly used in 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, it is to contain the tizanidine and derivant is the often release part of active component and the preparation that slow-released part is prepared from.
Wherein, the often release part is in the slow-released part skin in the mix preparation of often release part and slow-released part, makes the often release part than the first release of slow-released part.
Further, the tizanidine and the derivant mol ratio thereof that are contained of often release part and slow-released part is 5～95: 5～95.
Further preferred, tizanidine that often release part and slow-released part are contained and derivant mol ratio thereof are 35～75: 25～65.
Further preferred again, tizanidine that often release part and slow-released part are contained and derivant mol ratio thereof are 65～75: 25～35.
Tizanidine and derivant optimum mole ratio thereof that preferred often release part and slow-released part are contained are 70: 30.
Novel form of the present invention uses tizanidine's derivant to be tizanidine hydrochloride, nitric acid tizanidine, sulphuric acid tizanidine, fumaric acid tizanidine, citric acid tizanidine, methanesulfonic acid tizanidine, p-methyl benzenesulfonic acid tizanidine etc.
Preferred tizanidine hydrochloride.
The often release part of novel form of the present invention and the mix preparation of slow-released part are solid preparations such as tablet, capsule or pill.
Preferred tablet is a double-layer tablet.
Another technical problem to be solved by this invention provides the preparation method of aforementioned pharmaceutical compositions.
The preparation method of novel form of the present invention comprises the steps:
A, get tizanidine's or derivatives thereof, be divided into 5～95: 5～95 two parts in molar ratio;
B, to get the mol ratio umber be that tizanidine's or derivatives thereof of 5～95 adds pharmaceutically acceptable slow-released part adjuvant and is prepared into slow-released part internal layer label or granule;
C, to get the mol ratio umber be that tizanidine's or derivatives thereof of 5～95 adds pharmaceutically acceptable often release part adjuvant and is prepared into the often release part, is coated on step b gained label or granule skin, coating, promptly.
Coating of the present invention can directly use as preparation; Also can on the basis of this coating, add acceptable accessories or complementary composition and be prepared into preparation pharmaceutically commonly used.
The slow-released part adjuvant of novel form of the present invention 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.
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 solid dispersion of the present invention is selected water-solubility carriers such as PEG, PVP for use.
Described disintegrating agent is low-substituted hydroxypropyl methylcellulose (L-HPC), crospolyvinylpyrrolidone (PPVP), carboxymethyl starch sodium (CMS-Na) and composition thereof.
Filler can be selected starch, Icing Sugar, dextrin, lactose, amylum pregelatinisatum, microcrystalline Cellulose, inorganic salts, mannitol, xylitol, sorbitol etc.
Adhesive comprises distilled water, ethanol, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hypromellose, 5%～20% gelatin solution, 50%～70% sucrose solution, 3%～5% polyethylene adjoin the aqueous solution of pyrrolidone (PVP) or alcoholic solution etc.
Correctives can be selected natural or artificial sweetening agents such as edulcorant protein sugar, aspartame or aromatic Mentholum, acidic flavoring agent citric acid, essence, mannitol, stevioside.
Lubricant can be selected magnesium stearate, micropowder silica gel, Stepanol MG, Pulvis Talci hydrogenated vegetable oil, polyethylene glycols and magnesium laurylsulfate etc.
Coloring agent comprises, pharmaceutically available color lake and pigments such as ferrum oxide, titanium dioxide, sunset yellow, tartrazines, capsanthin, carotene, fast green, chlorophyll.
Tizanidine 0.5～16mg is contained in every preparation unit in the novel form of the present invention.Wherein the tizanidine can convert and can get according to both mol ratios in often release part and the slow-released part.
Prove that according to the test of pesticide effectiveness medicine composite for curing effect of the present invention 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.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement and the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The specific embodiment
The preparation of embodiment 1 tablet of the present invention (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) 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 internal layer label;
B, get tizanidine hydrochloride 1.4g, add microcrystalline Cellulose and make the often release part, be coated on step a gained label skin, coating;
C, get step b gained coating, add starch according to a conventional method tabletting be prepared from.
The preparation of embodiment 2 tablets of the present invention (tizanidine's mol ratio is 65: 35 in often release part and the slow-released part)
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 internal layer label;
B, get tizanidine hydrochloride 2.6g, add dextrin and make the often release part, be coated on step a gained label skin, coating;
C, get step b gained coating, add starch, correctives according to a conventional method tabletting be prepared from.
The preparation of embodiment 3 tablets of the present invention (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 internal layer label;
B, get tizanidine hydrochloride 3.0g, add microcrystalline Cellulose and make the often release part, be coated on step a gained label skin, coating;
C, get step b gained coating, add starch according to a conventional method tabletting be prepared from.
The preparation of embodiment 4 tablets of the present invention (tizanidine's mol ratio is 66: 34 in often release part and the slow-released part)
Raw material: tizanidine hydrochloride 2g, sodium alginate 25g, methylcellulose 50g, carboxymethyl cellulose 25g, an amount of, the corn starch 100g (1000) of 75% alcoholic solution, 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 internal layer label;
B, get tizanidine hydrochloride 1.32g, add corn starch and make the often release part, be coated on step a gained label skin, coating;
C, get step b gained coating, add corn starch according to a conventional method tabletting be prepared from.
The preparation of embodiment 5 tablets of the present invention (tizanidine's mol ratio is 70: 30 in often release part and the slow-released 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 internal layer label;
B, get sulphuric acid tizanidine 5.6g, add corn starch and make the often release part, be coated on step a gained label skin, coating;
C, get step b gained coating, add starch and dextrin according to a conventional method tabletting be prepared from.
The preparation of embodiment 6 capsules of the present invention (tizanidine's mol ratio is 70: 30 in often release part and the slow-released part)
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 the slow-released part inner layer granule;
B, get citric acid tizanidine 3.5g, add corn starch and make the often release part, 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.
The preparation of embodiment 7 granules of the present invention (tizanidine's mol ratio is 70: 30 in often release part and the slow-released part)
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, method for making is as follows:
A, get fumaric acid tizanidine 0.6g, add hydroxypropyl emthylcellulose (HPMC K4M), be prepared into the slow-released part inner layer granule;
B, get fumaric acid tizanidine 1.4g, add lactose and make the often release part, be coated on step a gained granule skin, coating;
C, get step b gained coating, add lactose and be prepared into wet granular, drying.
The preparation of embodiment 8 tablets of the present invention (tizanidine's mol ratio is 5: 95 in often release part and the slow-released part)
Raw material: tizanidine hydrochloride 2g, sodium carboxymethyl cellulose 60.6g, lactose 120g, starch 103g, microcrystalline Cellulose 8g, 75% ethanol an amount of (1000), method for making is as follows:
A, get tizanidine hydrochloride 1.9g, add sodium carboxymethyl cellulose and lactose, be prepared into slow-released part internal layer label;
B, get tizanidine hydrochloride 0.1g, add microcrystalline Cellulose and make the often release part, be coated on step a gained label skin, coating;
C, get step b gained coating, add starch according to a conventional method tabletting be prepared from.
The preparation of embodiment 9 tablets of the present invention (tizanidine's mol ratio is 95: 5 in often release part and the slow-released part)
Raw material: tizanidine hydrochloride 2g, ethyl cellulose 54.3g, lactose 90g, starch 120g, microcrystalline Cellulose 7g, 75% ethanol an amount of (1000), method for making is as follows:
A, get tizanidine hydrochloride 0.1g, add ethyl cellulose and lactose, be prepared into slow-released part internal layer label;
B, get tizanidine hydrochloride 1.9g, add microcrystalline Cellulose and make the often release part, be coated on step a gained label skin, coating;
C, get step b gained coating, add starch according to a conventional method tabletting be prepared from.
The preparation of embodiment 10 tablets of the present invention (tizanidine's mol ratio is 35: 65 in often release part and the slow-released part)
Raw material: tizanidine hydrochloride 2g, polypropylene 74.8g, lactose 115g, starch 106g, microcrystalline Cellulose 3g, 75% ethanol 17ml (1000), method for making is as follows:
A, get tizanidine hydrochloride 1.3g, add polypropylene and lactose, be prepared into slow-released part internal layer label;
B, get tizanidine hydrochloride 0.7g, add microcrystalline Cellulose and make the often release part, be coated on step a gained label skin, coating;
C, get step b gained coating, add starch according to a conventional method tabletting be prepared from.
Below prove beneficial effect of the present invention by pharmacodynamics test.
Test example 1: the screening test of often release part and slow release slow release proportioning in tizanidine's novel form of the present invention
Trial drug: tizanidine's mol ratio was respectively 5: 95,35: 65,65: 35,70: 30,75: 25,95: 5 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 follow 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 placebo respectively, tizanidine's mol ratio (5: 95) group in often release part and the slow-released part, tizanidine's mol ratio (65: 35) group in often release part and the slow-released part, tizanidine's mol ratio (70: 30) group in often release part and the slow-released part, tizanidine's mol ratio (35: 65) group in often release part and the slow-released part, tizanidine's mol ratio (75: 25) group in often release part and the slow-released part, tizanidine's mol ratio (95: 5) group in often release part and the slow-released part, (specification is 4mg to tizanidine's conventional formulation group, 3 times/day) and tizanidine's slow releasing preparation group (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
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 (95: 5) is organized, is compared in tizanidine's mol ratio (75: 25) group in tizanidine's mol ratio (70: 30) group in tizanidine's mol ratio (65: 35) group in tizanidine's mol ratio (35: 65) group in tizanidine's mol ratio (5: 95) group in tizanidine's conventional formulation group, often release part and the slow-released part, often release part and the slow-released part, often release part and the slow-released part, often release part and the slow-released part, 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 the present invention preferred tizanidine often release part and slow-released part is 70: 30.
The novel form of tizanidine of the present invention 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 (9)
1. the dosage form of tizanidine's or derivatives thereof is characterized in that: it is to contain the preparation that often release part that tizanidine's or derivatives thereof is an active component and slow-released part are prepared from;
Wherein, tizanidine's or derivatives thereof mol ratio of being contained of described often release part and slow-released part is 5～95: 5～95;
Wherein, described slow-released part is internal layer label or granule, and the often release part is wrapped in the slow-released part skin; The adjuvant of described slow-released part is: hydroxypropyl emthylcellulose, tragcanth, methylcellulose, sodium alginate, sodium carboxymethyl cellulose, ethyl cellulose, polypropylene.
2. dosage form according to claim 1 is characterized in that: tizanidine's or derivatives thereof mol ratio that described often release part and slow-released part are contained is 35～75: 25～65.
3. dosage form according to claim 2 is characterized in that: tizanidine's or derivatives thereof mol ratio that described often release part and slow-released part are contained is 65～75: 25～35.
4. dosage form according to claim 3 is characterized in that: tizanidine's or derivatives thereof mol ratio that described often release part and slow-released part are contained is 70: 30.
5. according to each described dosage form of claim 1～4, it is characterized in that: described tizanidine's derivant is a tizanidine hydrochloride.
6. dosage form according to claim 5 is characterized in that: the mix preparation of described often release part and slow-released part is tablet, capsule or pill.
7. dosage form according to claim 6 is characterized in that: described tablet is a double-layer tablet.
8. method for preparing the described dosage form of claim 1, it comprises the steps:
A, get tizanidine's or derivatives thereof, be divided into 5～95: 5～95 two parts in molar ratio;
B, to get the mol ratio umber be that tizanidine's or derivatives thereof of 5～95 adds pharmaceutically acceptable slow-released part adjuvant and is prepared into slow-released part internal layer label or granule;
C, to get the mol ratio umber be that tizanidine's or derivatives thereof of 5～95 adds pharmaceutically acceptable often release part adjuvant and is prepared into the often release part, is coated on step b gained label or granule skin, coating.
9. the preparation method of dosage form according to claim 8 is characterized in that: get step c gained coating, add acceptable accessories or complementary composition and be prepared into preparation pharmaceutically commonly used.
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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 |