CN105582011A - Methylnaltrexone bromide solid composition and preparation method thereof - Google Patents
Methylnaltrexone bromide solid composition and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a methylnaltrexone bromide solid composition and a preparation method thereof. The solid composition comprises ingredients of methylnaltrexone bromide and an acidic stabilizing agent at a weight ratio being (10:1) to (1:10). The methylnaltrexone bromide solid composition has the advantages that the formula process is advanced; the product quality is stable; the problems of stability and the content uniformity of the methylnaltrexone bromide in the preparation process can be perfectly solved; and the problem of stability of a methylnaltrexone bromide preparation in the storage process can also be perfectly solved. The methylnaltrexone bromide solid composition invented by the research group has the beneficial effects that the solid preparation and the methylnaltrexone bromide injection on the market have the identical curative effect; the administration mode is changed into oral administration; the medicine administration compliance of a patient is improved; the production cost is reduced; the selling price of a product is reduced; and the economical burden of the patient is reduced. Therefore economic, safe, effective and convenient therapeutic medicine is provided for the patient with constipation due to opioid medicine, and good social benefits and economic benefits can be obtained.
Description
Technical field
The invention belongs to field of medicine preparations, particularly, the present invention relates to a kind of methylnaltrexone bromide solid composite and system thereofPreparation Method.
Background technology
Methylnaltrexone bromide (MethylnaltrexoneBromide, trade name Relistor) chemistry bromination-17-(cyclopropyl first by nameBase)-4,5 α-epoxy-3,14-dihydroxy-17-methyl-6-oxo morphinan. By subsidiary of Hui Shi Wyeth drugmaker of the U.S. andThe joint study exploitation of ProgenicsPharmaceuticals company, is peripheral mu opiate receptor antagonist, not through blood-brain barrier,Can maintain patient's normal stomach and intestine function, improve end-stage patients' quality of life. This product is used for the treatment of accepts entering of palliative treatmentThe constipation that malleability Disease causes because of opioid drug is used the situation that laxative medicine is invalid.
In April, 2008, Her Majesty the Queen in right of Canada as represented by the minister of Healt and U.S. FDA were ratified respectively the listing of methylnaltrexone bromide injection, and hypodermic injection, usesUse laxatives invalid in the treatment constipation (opioid-inducedconstipation, OIC) that causes of opioid drugSituation. Her Majesty the Queen in right of Canada as represented by the minister of Healt takes the lead in having ratified in the whole world this novel medicine. Methylnaltrexone bromide is within the scope of European Union, to get permission to useIn first medicine of opioid drug induction constipation, but its taboo is for known or be suspected to have mechanicalness intestines and stomach and block patient.
But injection administration brings pain to patient, and hypodermic injection often can produce excitant to skin, affects clothes for patientsThe compliance of medicine. Meanwhile, methylnaltrexone bromide, because itself is unstable, is easily degraded in preparation and storage process, impactProduct quality, produces drug safety hidden danger.
On the other hand, in pain therapy, opium kind analgesics accounts for 7 one-tenth of analgesic, and patient accepts opiates medicineWhen thing treatment, majority all can meet with constipation, and methylnaltrexone bromide is dived because its outstanding coupling result for the treatment of has huge marketPower, so current injection cost of manufacture is higher, has caused launch price more expensive, brings financial burden to many patients.
Therefore, current methylnaltrexone bromide pharmaceutical preparation still haves much room for improvement.
Summary of the invention
The present invention is intended to solve at least to a certain extent one of technical problem in correlation technique. For this reason, one of the present inventionObject is to propose a kind of methylnaltrexone bromide solid composite, and formulation and technology advanced person, and constant product quality can be perfectSolve stability problem and uniformity of dosage units problem that methylnaltrexone bromide occurs in preparation process, also can perfectly solve bromineFirst naltrexone preparation is depositing the stability problem occurring in process. And the methylnaltrexone bromide solid composite of this seminar invention,Solid pharmaceutical preparation has same curative effect with the methyhaaltrexone bromide injection of listing, makes oral administration into, improves taking medicine of patient and complies withProperty, and reduce production costs, reduce product price, alleviate patient's financial burden. Thereby for opioid drug causes justThat secret patient provides is a kind of economical, safety, effectively, medicine easily, can produce good social benefit and economic effectBenefit.
In one aspect of the invention, the present invention proposes a kind of methylnaltrexone bromide solid composite, it is characterized in that: described inIn solid composite, comprise one or more acid stabilizers, and the weight ratio of methylnaltrexone bromide and acid stabilizer 10:1～Within the scope of 1:10. This solid composite also comprises filler, adhesive, disintegrant, lubricant or other are pharmaceutically acceptableAuxiliary material.
The material that this solid composite comprises and weight portion thereof are: methylnaltrexone bromide (5～30), and acid stabilizer (0.8～86),Filler (7～90), adhesive (1～10), disintegrant (1～10), lubricant (0.1～1.5); More preferably bromine firstNaltrexone (8～24), acid stabilizer (2～24), filler (20～75), adhesive (2～8), disintegrant (2～5), lubricant (0.5～1.0).
The inventor studies with keen determination, has carried out great many of experiments to improve the stability of methylnaltrexone bromide. Found that, when locatingIn side, add a certain proportion of certain or some acid stabilizer, can ensure the stability of methylnaltrexone bromide in preparation process.If do not add acid stabilizer or additional proportion is improper, only in pelletizing press sheet process, the related substance of methylnaltrexone bromide is superMark.
According to embodiments of the invention, in described methylnaltrexone bromide solid composite, one or more acid stabilizers includeMachine acid, inorganic acid; Wherein organic acid is selected from tartaric acid, citric acid, malic acid, fumaric acid, maleic acid, lactic acid, sorbAcid, acetic acid, propionic acid, butanedioic acid, salicylic acid, oxalic acid, benzene sulfonic acid, cysteine hydrochloride, L-Aspartic acid, glutamic acidIn at least one, be preferably at least one in tartaric acid, citric acid, malic acid, cysteine hydrochloride, L-Aspartic acidKind, most preferably be at least one in tartaric acid, citric acid, L-Aspartic acid; Described inorganic acid be selected from hydrochloric acid, sulfuric acid,At least one in phosphoric acid, is preferably phosphoric acid.
According to embodiments of the invention, in described methylnaltrexone bromide solid composite, the weight of methylnaltrexone bromide and acid stabilizerMeasure than being preferably 5:1～1:5 more preferably 3:1～1:1. When the weight ratio of methylnaltrexone bromide and acid stabilizer is in preferable rangeIn, not only can ensure the stability of methylnaltrexone bromide in pelletizing press sheet process, and depositing its related substance in processAmplification also less. And in the time that the weight ratio of methylnaltrexone bromide and acid stabilizer is in more preferably scope, depositing in processIts related substance is miraculous only very small increase, has improved greatly the stability of said preparation.
According to embodiments of the invention, described filler is selected from sucrose, starch, microcrystalline cellulose, lactose, sweet mellow wine, pasteAt least one in essence, is preferably at least one in lactose, microcrystalline cellulose, sweet mellow wine, more preferably sweet mellow wine.
According to embodiments of the invention, described binder is selected from starch slurry, methylcellulose, hydroxypropyl cellulose, hydroxypropyl firstAt least one in cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol, is preferably hydroxypropyl first fiberAt least one in element, hydroxypropyl cellulose, polyvinylpyrrolidone, more preferably hydroxypropyl cellulose.
According to embodiments of the invention, described disintegrant be selected from Ac-Di-Sol, low-substituted hydroxypropyl cellulose,At least one in PVPP, sodium carboxymethyl starch, is preferably Ac-Di-Sol, low substituted hydroxy-propyl fibreAt least one in dimension element, more preferably Ac-Di-Sol.
According to embodiments of the invention, described lubricant is selected from talcum powder, lauryl sodium sulfate, silica, stearic acidAt least one in magnesium, calcium stearate, Macrogol 4000, Macrogol 6000, be preferably talcum powder, silica,At least one in dolomol, more preferably at least one in dolomol, talcum powder.
Prove as embodiments of the invention part, in the embodiment of the present invention, added the prescription of acid stabilizer, in preparationAll be better than not adding in comparative example the prescription of acid stabilizer with the stability in storage process.
In another aspect of this invention, the invention provides the preparation method who prepares methylnaltrexone bromide composition. The method is simpleFeasible, can ensure that again methylnaltrexone bromide is stable, tablet content homogeneous.
According to embodiments of the invention, the described method of preparing methylnaltrexone bromide solid composite is wet granule compression tablet method. RootAccording to specific embodiments of the invention, described wet-granulation process is preparation binder solution; The mixing of sieving of all the other powder; Make softMaterial; Granulate; Dry; Compressing tablet.
According to embodiments of the invention, the preparation method of described methylnaltrexone bromide solid composite, comprises acid stabilizerBe dissolved in and in binder solution, carry out wet granule compression tablet with main ingredient, or only acid stabilizer is dissolved in binder solution,Main ingredient mixes and carries out wet granulation with other auxiliary materials, a kind of preferably front method.
According to a particular embodiment of the invention, when wet granulation, cross 20 orders or 24 mesh sieves, preferred mistake 24 mesh sieves.
According to tool the present embodiment of the present invention, when compressing tablet, tablet pressure is 40～100N, preferably 50～70N.
Find through many experiments research, methylnaltrexone bromide solid pharmaceutical preparation is small dimension preparation, and the uniformity of dosage units of product is easy toOverrun, causes the defective of product quality. The inventor is through repetition test, surprised discovery in research process, whenIn prescription, add a certain proportion of certain or some acid stabilizer, and adopt acid stabilizer and main ingredient are dissolved in stickyIn mixture solution, carry out the preparation method of wet granule compression tablet, can perfectly solve tablet in preparation and storage process surelyQualitative question, and can perfectly solve the uniformity of dosage units problem of tablet.
In a third aspect of the present invention, the present invention proposes methylnaltrexone bromide solid composite in the purposes of preparing in medicine, instituteStating medicine is used for the treatment of and accepts the constipation that the progressivity Disease of palliative treatment causes because of opioid drug and use laxative medicineInvalid situation.
Detailed description of the invention
Describe embodiments of the invention below in detail. Embodiment described below is exemplary, only for explaining the present invention,And can not be interpreted as limitation of the present invention. Unreceipted concrete technology or condition in embodiment, according to the document in this areaDescribed technology or condition or carry out according to product description. The unreceipted person of production firm of agents useful for same or instrument, isCan be by the conventional products of commercial acquisition.
Conventional method
(1) assay method of methylnaltrexone bromide solid composite related substance
(1) chromatographic condition:
With octadecylsilane chemically bonded silica be filler; Taking 0.2% potassium dihydrogen phosphate-methyl alcohol (20:80) as mobile phase;Detection wavelength is 220nm; Flow velocity is 1.0ml per minute; Sample size 20ul;
(2) need testing solution preparation:
Get this product appropriate, add mobile phase and dissolve and dilute and make in every 1ml the approximately solution containing 0.5mg;
(3) reference substance solution preparation:
Precision measures in right amount, adds the quantitative dilution of mobile phase and makes the solution that approximately contains 5 μ g in every 1ml.
(2) Content uniformity test
(1) chromatographic condition:
With octadecylsilane chemically bonded silica be filler; Taking 0.2% potassium dihydrogen phosphate-methyl alcohol (20:80) as mobile phase;Detection wavelength is 280nm; Flow velocity is 1.0ml per minute; Sample size 20ul;
(2) need testing solution preparation:
Get 10 of test samples, in mortar, grind evenly, get appropriate powder, add mobile phase and dissolve and dilute and make every 1mlThe middle solution that approximately contains 0.5mg;
(3) reference substance solution preparation:
Precision measures in right amount, adds the quantitative dilution of mobile phase and makes the solution that approximately contains 0.5mg in every 1ml.
(3) mass spectrum condition
(1) liquid phase systems:
Surveyor highly effective liquid phase chromatographic system, the triple level Four bar of TSQQuantumDis-covery mass spectrograph, is furnished with EFIMist ion gun (ESI), Xcalibur1.4 liquid matter data workstation (Finnigan company of the U.S.);
(2) chromatographic condition:
Chromatographic column is AttimaC18 (2.1mm × 100mm, 5um); Mobile phase be acetonitrile-0.02% trifluoroacetic acid solution (50:50); Flow velocity is 0.3ml/min; Column temperature is 30 DEG C; Sample size is 5ul;
(3) mass spectrum condition:
Electric spray ion source (ESI source), spray voltage 3500eV; 300 DEG C of heated capillary temperature; Sheath gas (N2) pressure2310kPa, assisted gas (N2) pressure 1800kPa; Collision gas (Ar) pressure 0.15Pa; Cation mode detects; SweepThe mode of retouching, for selecting reaction monitoring (SRM), is 0.2S sweep time.
(4) plasma sample processing:
FP at room temperature melts, and in vortex shaker mixer, the about 30s of vortex, gets blood plasma 0.5ml, puts 1.5ml toolPlug centrifuge tube in, add inner mark solution (methanol solution of 2mg/l) 1.0ml, vortex 3min, 10000r/min (0 DEG C) fromHeart 15min, gets supernatant, then in the centrifugal 5min of 10000r/min (0 DEG C), gets supernatant, and sample introduction 5ul, carries out HPLC-MS analyzes.
The specific embodiment of patent of the present invention is as follows:
Embodiment 1 prepares methylnaltrexone bromide sheet
Adhesive is mixed with to 6% concentration, recipe quantity tartaric acid is dissolved in to binder solution, recipe quantity bromine first is receivedBent ketone is dissolved in above-mentioned solution; All the other auxiliary materials are crossed 80 mesh sieves, and sweet mellow wine and Ac-Di-Sol mix;Adhesive is added to above-mentioned mixed-powder softwood processed, cross 24 mesh sieves and granulate; Being dried to moisture is 1.34%, by above-mentionedGrain mixes rear tablet press machine compressing tablet with dolomol, No. 6 punchings, pressure 54N.
Embodiment 2 prepares methylnaltrexone bromide sheet
Adhesive is mixed with to 8% concentration, recipe quantity citric acid is dissolved in to binder solution, recipe quantity bromine first is receivedBent ketone is dissolved in above-mentioned solution; All the other auxiliary materials are crossed 80 mesh sieves, and pre-paying starch and PVPP mix; To glueMixture adds above-mentioned mixed-powder softwood processed, crosses 24 mesh sieves and granulates; Being dried to moisture is 2.05%, by above-mentioned particle withLauryl sodium sulfate mixes rear tablet press machine compressing tablet, No. 6.5 punchings, pressure 50N.
Embodiment 3 prepares methylnaltrexone bromide sheet
Adhesive is mixed with to 5% concentration, recipe quantity L-Aspartic acid is dissolved in to binder solution, by recipe quantity bromineFirst naltrexone is dissolved in above-mentioned solution; All the other auxiliary materials are crossed 60 mesh sieves, and lactose and Hydroxypropyl methylcellulose mix; To glueMixture adds above-mentioned mixed-powder softwood processed, crosses 20 mesh sieves and granulates; Being dried to moisture is 2.17%, by above-mentioned particle withTalcum powder mixes rear tablet press machine compressing tablet, No. 5.5 punchings, pressure 62N.
Embodiment 4 prepares methylnaltrexone bromide sheet
Adhesive is mixed with to 7% concentration, recipe quantity phosphoric acid is dissolved in to binder solution, recipe quantity bromine first is received to songKetone is dissolved in above-mentioned solution; All the other auxiliary materials are crossed 100 mesh sieves, and microcrystalline cellulose and carboxyrnethyl starch sodium mix; By bondingAgent adds above-mentioned mixed-powder softwood processed, crosses 24 mesh sieves and granulates; Being dried to moisture is 1.34%, by above-mentioned particle and twoTablet press machine compressing tablet after silica closes evenly, No. 6 punchings, pressure 70N.
While investigating methylnaltrexone bromide and acid stabilizer different proportion, the impact (contrasting with embodiment 1) on related substance
Comparative example 1 prepares methylnaltrexone bromide sheet
Adhesive is mixed with to 6% concentration, recipe quantity methylnaltrexone bromide is dissolved in to above-mentioned solution; All the other auxiliary materials cross 80Mesh sieve, sweet mellow wine and Ac-Di-Sol mix; Adhesive is added to above-mentioned mixed-powder, cross 24 ordersSieve series grain; Being dried to moisture is 1.36%, above-mentioned particle is mixed to rear tablet press machine compressing tablet with dolomol, No. 6 punchings,Pressure 56N.
Comparative example 2 prepares methylnaltrexone bromide sheet
Adhesive is mixed with to 6% concentration, recipe quantity tartaric acid is dissolved in to binder solution, recipe quantity bromine first is receivedBent ketone is dissolved in above-mentioned solution; All the other auxiliary materials are crossed 80 mesh sieves, and sweet mellow wine and Ac-Di-Sol mix;Adhesive is added to above-mentioned mixed-powder softwood processed, cross 24 mesh sieves and granulate; Being dried to moisture is 1.33%, by above-mentionedGrain mixes rear tablet press machine compressing tablet with dolomol, No. 6 punchings, pressure 54N.
Comparative example 3 prepares methylnaltrexone bromide sheet
Adhesive is mixed with to 6% concentration, recipe quantity tartaric acid is dissolved in to binder solution, recipe quantity bromine first is receivedBent ketone is dissolved in above-mentioned solution; All the other auxiliary materials are crossed 80 mesh sieves, and sweet mellow wine and Ac-Di-Sol mix;Adhesive is added to above-mentioned mixed-powder softwood processed, cross 24 mesh sieves and granulate; Being dried to moisture is 1.32%, by above-mentionedGrain mixes rear tablet press machine compressing tablet with dolomol, No. 6 punchings, pressure 55N.
Investigate the impact (with embodiment 1 contrast) of wet granulation different process on methylnaltrexone bromide related substance
Comparative example 4 prepares methylnaltrexone bromide sheet
Adhesive is mixed with to 6% concentration, recipe quantity methylnaltrexone bromide is dissolved in to binder solution; All the other auxiliary material mistakes80 mesh sieves, sweet mellow wine, Ac-Di-Sol and tartaric acid mix; Adhesive is added to above-mentioned mixed powderEnd softwood processed, crosses 24 mesh sieves and granulates; Being dried to moisture is 1.36%, after above-mentioned particle is mixed with dolomolTablet press machine compressing tablet, No. 6 punchings, pressure 53N.
Investigate the impact (with embodiment 1 contrast) of wet granulation different process on methylnaltrexone bromide uniformity of dosage units
Comparative example 5 prepares methylnaltrexone bromide sheet
Adhesive is mixed with to 6% concentration, recipe quantity tartaric acid is dissolved in to binder solution; All the other auxiliary materials cross 80Mesh sieve, sweet mellow wine, Ac-Di-Sol and tartaric acid mix; Adhesive is added to above-mentioned mixed-powder,Crossing 24 mesh sieves granulates; Being dried to moisture is 1.36%, above-mentioned particle is mixed to rear tablet press machine compressing tablet with dolomol,No. 6 punchings, pressure 55N.
Embodiment 4 influence factor tests are investigated
Getting methylnaltrexone bromide sheet prepared by embodiment 1 and the methylnaltrexone bromide sheet of comparative example's 2,3,4 preparations carries outInfluence factor test, with reference to Chinese pharmacopoeia two annex X IX C bulk drugs of version in 2010 and pharmaceutical preparation stability testGuideline. Investigate respectively the stability under illumination 4500XL, 60 DEG C of high temperature and high humidity 92.5% condition, detailed resultsIn table 1, table 2.
Impact on related substance when table 1 methylnaltrexone bromide and acid stabilizer different proportion
From upper table data: in the time not adding acid stabilizer (comparative example 1), only in pelletizing press sheet process, bromine first is receivedThe related substance of bent ketone just sharply increases, and always assortedly reaches 2.048% and exceed standard, thus comparative example 1 do not continue again to place intoThe test of row influence factor.
In the time that the ratio of methylnaltrexone bromide and acid stabilizer is within the scope of 10:1～1:10 (comparative example 3), press granulatingThe related substance that can ensure methylnaltrexone bromide in sheet process can not exceed standard, and always mixing is 0.741%, but in influence factor testHeat, light are placed 10 days, total assorted reach respectively 1.493%, 1.479% and have approached limit.
In the time that the ratio of methylnaltrexone bromide and acid stabilizer is within the scope of 5:1～1:5 (comparative example 2), at pelletizing press sheetThe related substance that can ensure methylnaltrexone bromide in process can not exceed standard, and total mixing is only 0.301%, in influence factor test,Related substance amount of increase is also less.
In the time that the ratio of methylnaltrexone bromide and acid stabilizer is within the scope of 3:1～1:1 (embodiment 1), not only at pelletizing press sheetThe related substance that can ensure methylnaltrexone bromide in process is very small, and in influence factor test, related substance also miraculouslySubstantially do not increase.
The impact of table 2 wet granulation different process on methylnaltrexone bromide related substance
From upper table data: acid stabilizer and main ingredient are dissolved in and in binder solution, carry out wet granule compression tablet, orOnly acid stabilizer is dissolved in binder solution, main ingredient mixes and carries out wet granulation with other auxiliary materials, all can prepare steadyQualitative qualified methylnaltrexone bromide solid composite. But the tablet that before adopting, a kind of method is prepared is sent out through factors influencingExisting, stability is better than the latter.
Embodiment 5 uniformity of dosage units experiments
Getting methylnaltrexone bromide sheet prepared by methylnaltrexone bromide sheet prepared by embodiment 1 and comparative example 5, to carry out content equalEvenness experiment, carries out uniformity of dosage units inspection with reference to two annex X E Content uniformity tests of Chinese pharmacopoeia version in 2010Survey.
The impact of table 3 wet granulation different process on methylnaltrexone bromide uniformity of dosage units
| Lot number | Uniformity of dosage units |
| Embodiment 1 | 2 |
| Comparative example 5 | 8 |
From upper table data: main ingredient is dissolved in and in binder solution, carries out wet granule compression tablet, or only by main ingredient and itsHe carries out wet granulation at auxiliary material mixing, all can prepare the methylnaltrexone bromide solid composite that uniformity of dosage units is qualified. But frontThe tablet content uniformity that person prepares is better than the latter.
Embodiment 6 accelerates experiment and investigates
Get methylnaltrexone bromide sheet and commercially available parenteral solution prepared by embodiment 1, be placed in 40 DEG C ± 2 DEG C of temperature, relative humidityIn 75% ± 5% environment, in the the 1st, 2,3, measure related index June.
Table 4 methylnaltrexone bromide self-control tablet and commercially available parenteral solution accelerated test result
From upper table data: commercial preparation is 0.043% accelerating after June that maximum singly mixes, and always mixing is 0.137%, andSelf-control preparation is 0.025% accelerating after 6 months that maximum singly mixes, and always mixing is 0.093%. The maximum list of self-control preparation assorted andTotal mixing is all less than commercial preparation, and the stability of making as seen preparation by oneself is better than commercial preparation.
Embodiment 7 methylnaltrexone bromide sheets are the test of absolute bioavailability in the beagle dog body after 1 day in fasting
Be subject to test preparation: embodiment 1 methylnaltrexone bromide sheet is as being subject to test preparation;
Reference preparation: the methyhaaltrexone bromide injection having gone on the market of commodity RELISTOR by name;
Experimental program: healthy 6 of male Beagle dogs (body weight 14-15kg), be divided into 3 groups, 1 every group, adopt double crossFork is tested design, and the hypodermic injection of Beagle dog gives reference preparation, and oral administration is given and is subject to test preparation. Fasting 1 before administrationMy god, after administration, giving 50ml running water, administration can give feed after 4 hours. Before administration (0 hour), after administration0.5,1,2,3,4,5,6,8,10,24 hour, get blood 3mL through dog forelimb veniplex, after organic solvent is processedAdopt Liquid Chromatography-Tandem Mass Spectrometry method to measure the concentration of retigabine in dog serum, pharmacokinetic parameter usesWinNonlinTM (5.3 editions) calculates according to non-compartment model, the results are shown in Table 5.
The male Beagle dog of table 5 is oral give reference preparation or be subject to test preparation after the pharmacokinetic parameters of retigabine
F (relative bioavailability)=AUC (being subject to test preparation)0-24h/ AUC (reference preparation)0-24h×100％
Pharmacokinetics experimental result shows, the absolute bioavailability that is subject to test preparation is 77.87%, had by test preparation higherOral administration biaavailability, methylnaltrexone bromide is suitable for exploitation becomes oral solid formulation.
The effectiveness study of embodiment 8 methylnaltrexone bromide solid composite treatment constipation
30 of Thirty male rats, weight is (130 ± 10) g. The modeling of rat Constipation Model, 3d presses continuously3.0mg/kg weight gavage Loperamide (it is 0.9% physiological saline that Loperamide is dissolved in 1.0mL mass fraction) is made constipationModel. By successful modeling 30 rats, be divided at random 3 groups, 10 every group, be respectively: first group of (model contrastGroup), second group (commercially available methyhaaltrexone bromide injection), the 3rd group (self-control methylnaltrexone bromide solid composite).
During Constipation Model modeling 3d and given the test agent filling hello 7d, record rat feed intake (mL), amount of drinking water (mL), bodyThe fresh quality of fecal grains, ight soil and the dry mass of mass incremental (g), last 24h, calculate dejecta moisture by formula (1).
In formula: mfFor the fresh quality/g of ight soil; mdFor ight soil dry mass/g.
Adopt SPSS20.0 software kit to carry out statistical analysis to the data obtained, each group compares with variance (ANOVA),Adopt Duncanny ' smultiplerangetest methods analyst. During as significant difference more further with the new changeable territory of Deng KenshiDifference between analyzing and processing mean, data withRepresent, P < 0.05 has statistical significance for difference.
At whole experimental session, the equal normal growth of rat, there is not rat diarrhoea phenomenon in experimental session, shows Wistar ratConstipation Model modeling success. As shown in Table 5, model control group feed intake, amount of drinking water, weight increment, fecal grains withAnd dejecta moisture be all starkly lower than commercial preparation group with self-control preparation group (P < 0.05), this illustrates two kinds of methylnaltrexone bromide preparationsAll can well treat constipation. Commercial preparation group and feed intake, amount of drinking water, weight increment, the ight soil of making preparation group by oneselfGrain number and dejecta moisture there are no significant difference (P > 0.05), the curative effect there was no significant difference of two kinds of preparations of this explanation.
The feed intake of table 6 Normal group and model control group, amount of drinking water, weight increment,Fecal grains and dejecta moisture comparison (,n＝10)
| Index | Model control group | Commercial preparation group | Self-control preparation group |
| Feed intake/g | 60.13±7.84 | 78.56±5.12 | 80.33±8.36 |
| Amount of drinking water/mL | 90.14±18.74 | 149.52±20.8 | 147.46±19.7 |
| Weight increment/g | 2.23±5.89 | 14.89±2.15 | 14.77±5.62 |
| Fecal grains | 20.74±5.61 | 43.12±8.01 | 44.38±6.19 |
| Dejecta moisture/% | 30.45±2.16 | 56.31±4.41 | 54.98±6.19 |
In description of the invention, it will be appreciated that, term " first ", " second " be only for describing object, and can notBe interpreted as instruction or hint relative importance or the implicit quantity that indicates indicated technical characterictic. Be limited with thus, " theOne ", one or more these features can be expressed or impliedly be comprised to the feature of " second ". In description of the invention,The implication of " multiple " is two or more, unless otherwise expressly limited specifically.
In the description of this description, reference term " embodiment ", " some embodiment ", " example ", " concrete example ",Or the description of " some examples " etc. means specific features, structure, material or the feature described in conjunction with this embodiment or exampleBe contained at least one embodiment of the present invention or example. In this manual, needn't to the schematic statement of above-mentioned termMust for be identical embodiment or example. And specific features, structure, material or the feature of description can be in officeIn one or more embodiment or example with suitable mode combination. In addition, not conflicting in the situation that, this areaTechnical staff can tie the feature of the different embodiment that describe in this description or example and different embodiment or exampleClose and combine.
Although illustrated and described embodiments of the invention above, be understandable that, above-described embodiment is exemplary,Can not be interpreted as limitation of the present invention, those of ordinary skill in the art within the scope of the invention can be to above-described embodimentChange, amendment, replacement and modification.
Claims (10)
1. a methylnaltrexone bromide solid composite, is characterized in that, described solid composite comprises methylnaltrexone bromide and acidityStabilizing agent, the weight ratio of described methylnaltrexone bromide and acid stabilizer is 10:1～1:10.
2. solid composite according to claim 1, is characterized in that, described methylnaltrexone bromide and acid stabilizerWeight ratio is preferably 5:1～1:5, more preferably 3:1～1:1.
3. solid composite according to claim 1, is characterized in that, described acid stabilizer is organic acid and/or nothingMachine acid; Wherein said organic acid for be selected from tartaric acid, citric acid, malic acid, fumaric acid, maleic acid, lactic acid, sorbic acid,In acetic acid, propionic acid, butanedioic acid, salicylic acid, oxalic acid, benzene sulfonic acid, cysteine hydrochloride, L-Aspartic acid, glutamic acidAt least one, be preferably at least one in tartaric acid, citric acid, malic acid, cysteine hydrochloride, L-Aspartic acid,Most preferably be at least one in tartaric acid, citric acid, L-Aspartic acid; Described inorganic acid is for being selected from hydrochloric acid, sulfuric acid, phosphorusAt least one in acid, is preferably phosphoric acid.
4. solid composite according to claim 1, is characterized in that, described composition contain filler, adhesive,Disintegrant, lubricant or other pharmaceutically acceptable auxiliary materials.
5. solid composite according to claim 4, is characterized in that, described filler is selected from sucrose, starch, micro-At least one in crystal fiber element, lactose, sweet mellow wine, dextrin, is preferably in lactose, microcrystalline cellulose, sweet mellow wine extremelyFew a kind of, more preferably sweet mellow wine.
6. solid composite according to claim 4, is characterized in that, described adhesive is selected from starch slurry, methyl fibreIn dimension element, hydroxypropyl cellulose, Hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycolAt least one, be preferably at least one in Hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, more preferablyFor hydroxypropyl cellulose.
7. solid composite according to claim 4, is characterized in that, described disintegrant is selected from cross-linked carboxymethyl fiberAt least one in element sodium, low-substituted hydroxypropyl cellulose, PVPP, sodium carboxymethyl starch, is preferably crosslinked carboxylic firstAt least one in base sodium cellulosate, low-substituted hydroxypropyl cellulose, more preferably Ac-Di-Sol,
Alternatively, described lubricant be selected from talcum powder, lauryl sodium sulfate, silica, dolomol, calcium stearate,At least one in Macrogol 4000, Macrogol 6000, is preferably in talcum powder, silica, dolomolAt least one, more preferably at least one in dolomol, talcum powder.
8. solid composite according to claim 1, is characterized in that, comprising:
Optionally, described solid composite comprises:
9. a method of preparing the methylnaltrexone bromide solid composite described in claim 1-8 any one, comprising: preparation is stickyMixture solution; Methylnaltrexone bromide and acid stabilizer are added in described binder solution and mixed; Softwood processed; Granulate; Dry;Compressing tablet,
Wherein, further comprise: before carry out described softwood processed, to adding described methylnaltrexone bromide and acid stabilizerIn binder solution, add at least one of filler, adhesive, disintegrant and lubricant,
Optionally, described granulation was 20 orders or 24 mesh sieves, preferred mistake 24 mesh sieves;
Optionally, the pressure adopting when described compressing tablet is 40～100N, preferably 50～70N.
Described in claim 1-8 any one methylnaltrexone bromide solid composite in the purposes of preparing in medicine, described medicineBe used for the treatment of the constipation of the progressivity Disease of accepting palliative treatment because using opioid drug to cause.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106177903A (en) * | 2016-07-25 | 2016-12-07 | 成都国弘医药有限公司 | Nalmefene hydrochloride and the pharmaceutical composition of two kinds of active ingredient of reduced glutathion |
| CN108976240A (en) * | 2017-06-02 | 2018-12-11 | 扬子江药业集团有限公司 | A kind of refining methd of methylnaltrexone bromide |
| CN108976240B (en) * | 2017-06-02 | 2021-03-02 | 扬子江药业集团有限公司 | Refining method of methylnaltrexone bromide |
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| WO2021041740A1 (en) * | 2019-08-28 | 2021-03-04 | Delpor, Inc. | Compositions of opioid antagonists, implant devices, and treatment methods for opioid use disorder |
| WO2021041730A1 (en) * | 2019-08-28 | 2021-03-04 | Delpor, Inc. | Compositions for small molecule therapeutic agent compounds |
| CN114641291A (en) * | 2019-08-28 | 2022-06-17 | 戴尔普尔有限公司 | Compositions of Small Molecule Therapeutic Compounds |
| CN112741813A (en) * | 2021-02-08 | 2021-05-04 | 北京佗林医药科技有限公司 | Naltrexone binary subcutaneous implant and preparation method thereof |
| WO2023031955A1 (en) * | 2021-08-28 | 2023-03-09 | Redasani Vijayendrakumar Virendrakumar Ji | Oral pharmaceutical compositions of methylnaltrexone and salt thereof |
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